ELECTROMOTIVE DRUG ADMINISTRATION OF LIDOCAINE TO ANESTHETIZE THE BLADDER BEFORE INTRAVESICAL CAPSAICIN

Purpose

The discomfort caused by intravesical capsaicin during instillation may restrict its use in some patients. We studied the effectiveness of using electromotive drug administration (EMDA) of lidocaine to anesthetize the bladder before capsaicin.

Materials and Methods

EMDA of lidocaine and epinephrine was performed in 8 patients with detrusor hyperreflexia using catheters, electrodes and an electrical current generator (20 mA., 15 minutes) followed immediately by intravesical capsaicin (2 mmol./l.) for 30 minutes under urodynamic monitoring. The patients scored suprapubic pain at 5 minutes and at the end of the capsaicin instillations on a scale of 0 to 10. Of the 8 patients 5 had had previous capsaicin treatments and the scores were compared to previous scores when intravesical lidocaine without EMDA had been used as local anesthesia before capsaicin.

Results

The pain scores during capsaicin instillations after EMDA of lidocaine were much lower than those during capsaicin instillations after lidocaine alone. EMDA virtually eliminated the hyperreflexic contractions of the bladder occurring during capsaicin instillations, thus reducing the risk of urethral leakage, and prevented autonomic dysreflexia that had previously occurred in 1 patient.

Conclusions

EMDA of lidocaine is an effective means of reducing pain during subsequent intravesical capsaicin, which makes the use of capsaicin in the treatment of detrusor hyperreflexia more acceptable.     

Evidence of a peripheral role of neurokinins in detrusor hyperreflexia: a further study of selective tachykinin antagonists in chronic spinal injured rats

PURPOSE: Spinal cord injury above the sacral micturition center usually leads to detrusor hyperreflexia, increased intravesical pressure and post-void residual urine. Detrusor hyperreflexia is believed to be mediated by afferent C fibers with tachykinins as neurotransmitters. We investigated the selective peptide tachykinin antagonists MEN 11420 and GR 82334 of NK-2 and NK-1 receptors, respectively, in a chronic rat model of detrusor hyperreflexia after suprasacral spinal cord injury. MATERIALS AND METHODS: Adult female Sprague-Dawley rats weighing 200 to 250 gm. were used. The spinal cord was transected at the T10 level. The bladder was evacuated by the Credé maneuver 3 times daily. After 6 weeks the rats were implanted with femoral vein and bladder dome catheters 2 days before filling cystometry. The 5 rats in group 1 received 100 nmol./kg. of the NK-2 antagonist MEN 11420 intravenously. The 5 rats in group 2 received 100 nmol./kg. of the NK-1 antagonist GR 82334 intravenously. The 5 rats in group 3 received a combination of the same dose of each antagonist. Three repetitive micturition cycles were recorded before injection. Three micturition cycles were done 20 minutes after the injection of each antagonist. Mean cystometric parameters were reported, including bladder capacity, micturition pressure, baseline pressure, post-void residual urine and micturition volume, and the number and amplitude of hyperreflexic contractions greater than 15 cm. water. RESULTS: MEN 11420 significantly reduced the frequency of hyperreflexic contractions and baseline bladder pressure (p <0.05). There was no statistically significant effect on the other cystometric parameters. GR 82334 reduced the amplitude of hyperreflexic contractions but not statistically significant. A combination of MEN 11420 and GR 82334 significantly reduced the frequency and amplitude of hyperreflexic contractions (p <0.05) with no significant effects on other cystometric parameters, although there was a tendency toward increased micturition volume and bladder capacity. CONCLUSIONS: These results suggest that at the peripheral level there is an efferent role of tachykinins in detrusor hyperreflexia after spinal cord injury. NK-1 and NK-2 receptor selective antagonists reduced the frequency and amplitude of hyperreflexic contractions as well as baseline bladder pressure. This finding may lead to potential new therapeutic modalities using selective tachykinins antagonists with other pharmacological agents to combat detrusor hyperreflexia.     

EFFECTS OF THE K+ CHANNEL OPENER, ZD6169, ON VOLUME AND PGE2-STIMULATED BLADDER ACTIVITY IN CONSCIOUS RATS

Purpose

To investigate the effects of the new K_ATP channel opener, ZD6169, shown to have an in vivo selectivity for the bladder, on bladder activity in rats.

Materials and Methods

ZD6169 was given intra-arterially (i.a., 0.1 and 1 mg./kg.) or orally (3 mg./kg.) to conscious Sprague-Dawley rats undergoing continuous cystometry. Investigations were also performed before and after stimulation of bladder activity by intravesical prostaglandin (PG) E₂.

Results

Intra-arterial ZD6169 increased residual volume, but caused no changes in other cystometric parameters. In rats receiving oral ZD6169, cystometric parameters were compared (every hour up to five hours) to those recorded in rats receiving oral vehicle. No differences were found, except in threshold pressure, which was significantly increased. Intravesical PGE₂ 20 micro M increased micturition and basal pressures, and decreased bladder capacity and micturition volume. ZD6169 1 mg./kg., given i.a., reduced or completely prevented the activity induced by intravesical PGE₂. Three hours after orally administered ZD6169 (3 mg./kg.), intravesical PGE₂ 20 micro M had no effect. Three hours after oral administration of vehicle, the effects of PGE₂ were attenuated, but still statistically significant.

Conclusions

ZD6169, given i.a. or orally, increased threshold pressure, but had otherwise little effect on volume-induced micturition. However, the drug markedly reduced or prevented PGE₂-induced bladder activity when given i.a.; it was also effective when given orally. If ZD6169 has inhibiting effects on bladder contraction in man without any cardiovascular actions, the drug may represent a novel, promising way of treating bladder overactivity.     

INTRAVESICAL CAPSAICIN AS A TREATMENT FOR REFRACTORY DETRUSOR HYPERREFLEXIA: A DUAL CENTER STUDY WITH LONG-TERM FOLLOWUP

Purpose

We described the long-term outcome of intravesical capsaicin instillations in patients with urinary incontinence and compared its efficacy in 2 similar populations of patients with multiple sclerosis in a dual center study.

Materials and Methods

During 5 years 79 patients with intractable urinary incontinence have been treated with intravesical capsaicin. The majority of patients had spinal cord disease due to multiple sclerosis but 4 were neurologically normal. Cystometry was performed before and 4 to 6 weeks after intravesical instillation of 1 to 2 mmol./l. of capsaicin in 30% ethanol in saline. Instillations of vehicle (30% ethanol in saline) alone were carried out in 5 patients.

Results

In patients with phasic detrusor hyperreflexia complete continence was achieved in 44%, satisfactory improvement occurred in 36% and treatment failed in 20%. Clinical benefit from a single instillation lasted 3 to 6 months and was repeated in some patients with similar improvement. Capsaicin was ineffective in patients with poor bladder compliance and in neurologically normal patients with sensory urgency and detrusor instability. There was no clinical or urodynamic improvement in patients treated with vehicle alone. There have been no long-term complications.

Conclusions

Our study shows that repeated instillations of intravesical capsaicin are effective in treatment of patients with detrusor hyperreflexia due to spinal cord disease and that effectiveness of the treatment persists at least 3 to 5 years.     

Effects of Nitric Oxide on Detrusor Relaxation

Purpose

Recently we (1994) reported the photo-induced adequate nitric oxide (PIANO) system, in which an NO- or NO₂-carrying molecule which has been photoactivated to release NO, could be exploited to investigate the role of NO in various smooth muscle functions. This study was designed to characterize the effect of nitric oxide (NO) exploiting PIANO on rat detrusor relaxation by isometric tension recording and measuring changes in cGMP content.

Materials and Methods

Exposure to ultraviolet light was used (1 to 60 seconds) to evoke PIANO in the presence of streptozotocin, an NO-carrier, and N^omega-nitro-L-arginine (L-NOARG), an NO₂-carrier. During relaxation the cyclic guanosine monophosphate (cGMP) content was measured by radioimmunoassay.

Results

Rat detrusor strips were reversibly relaxed upon NO generation via PIANO. Pyrogallol, an O₂ generator, significantly (p less than 0.01) diminished PIANO-mediated relaxation. During PIANO-mediated relaxation, the tissue level of cyclic GMP significantly (p less than 0.05) increased over that of the control. Furthermore, methylene blue, a guanylate cyclase inhibitor, significantly (p less than 0.01) inhibited both the relaxation and the increase of cGMP.

Conclusion

We concluded that rat detrusor muscle was capable of responding to NO, and these findings might lead to a treatment for bladder instability and detrusor hyperreflexia, by the use of intravesical instillation of NO donors.     

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.     

Extended voiding cystometry: technique and results of monitoring in patients with suprasacral spinal cord injury

Summary Extended voiding cystometry was performed for 3–10 h at the natural filling rate of 20 patients with complete suprasacral spinal cord injury and detrusor hyperreflexia and vesicosphicter dyssynergia who had normal upper tracts. This technique provided documentation of the frequency, duration, and amplitude of and the change in the intercontraction pressure during multiple physiologic voiding cycles. The percentage of time occupied by contractile activity and that during which intravesical pressures were >40 cmH₂O were also calculated. The detrusor activity in this patient group has not previously been reported. Although our patients demonstrated frequent (2.1 contractions/h) high-amplitude (56.8 cmH₂O), long (4 min/contraction) contractions and spent substantial time (13.8% of the time monitored) in contractile activity that maintained intravesical pressures of >40 cmH₂O (8.4%), they showed no evidence of upper tract disease. The five patients who underwent outlet procedures because of clinically problematic autonomic dysreflexia demonstrated a statistically significant postoperative decrease in contraction amplitude (P<0.01) and in time during which intravesical pressures were >40 cmH₂O (P<0.05). Extended voided cystometry enabled the measurement of detrusor contractility patterns and resting intravesical pressures that resulted from physiologic filling rates over an extended period, therefore providing considerably more information about detrusor activity than do conventional cystometric techniques.     

Urodynamic patterns after traumatic spinal cord injury

Objectives

To study the correlation between neurological level of spinal injury and bladder functions as detected by urodynamic study.

Study design

Analytical study.

Setting and participants

Seventy individuals with traumatic spinal cord injury (SCI) admitted to the Department of Physical Medicine and Rehabilitation, S.M.S. Medical College and Hospital, Jaipur. Detailed clinical, neurological evaluation as per American Spinal Injury Association Classification and radiological assessment were done along with clinical examination of bladder and urodynamic study.

Results

Out of 65 patients with suprasacral injuries, 53 (81.5%) demonstrated hyperreflexia with or without detrusor sphincter dyssynergia, 6 (9.2%) detrusor areflexia, and 6 (9.2%) had normal bladders, 41 (59.4%) low compliance (<20 ml/cmH₂O), and 47 (72.30%) had high detrusor leak pint pressures (>40 cmH₂O). Of the five patients with sacral injuries, one (20%) showed detrusor hyperreflexia, four (80%) detrusor areflexia, and one (20%) had low bladder compliance; all five (100%) had high detrusor leak point pressures.

Conclusions

The correlation between somatic neurologic findings, spinal imaging studies, and urodynamic findings in patients with SCI is not exact. Therefore, bladder management should not completely rely only on clinical bladder evaluation or neurological examination alone, but should always include urodynamic studies.     

URODYNAMIC EFFECTS OF INTRAVESICAL RESINIFERATOXIN IN HUMANS: PRELIMINARY RESULTS IN STABLE AND UNSTABLE DETRUSOR

Purpose

Resiniferatoxin, a substance isolated from some species of euphorbia, a cactus-like plant, presents pharmacological effects similar to those of capsaicin. We studied the urodynamic effects of intravesical resiniferatoxin* in normal subjects and patients with unstable detrusor contraction to provide insight into the action mechanism of the molecule on sensory neurons and possible future pharmacological and clinical use.

Materials and Methods

A total of 15 subjects with normal (8 patients) or unstable detrusor muscle (1 with detrusor instability and 6 with detrusor hyperreflexia) underwent urodynamic assessment during and after intravesical instillation of resiniferatoxin. Volume required to elicit the first desire to void, maximum bladder capacity and maximum bladder pressure were recorded during instillation of resiniferatoxin at a flow rate of 20 ml. per minute (normal subjects) or 15 minutes after instillation of 30 cc of a saline solution containing 10 sup −8 M. of resiniferatoxin and kept for 30 minutes in patients with unstable detrusor. The experiment was examined by the analysis of variance for repeated measures and post hoc comparisons were performed by Tukey-Kramer procedure. A p value <0.05 was accepted as significant.

Results

Resiniferatoxin did not decrease the volume required to elicit the first desire to void and did not produce warm or burning sensations at the suprapubic/urethral level during infusion in subjects with normal detrusor function. In patients with bladder hyperactivity mean bladder capacity increased from 175.28 ml. plus or minus standard deviation 36.05 to 280.85 ml. plus or minus standard deviation 93.33 (p <0.01) immediately after treatment, and no significant modification of bladder pressure was recorded. Four weeks after treatment, bladder capacity remained increased in 2 patients but mean capacity did not increase significantly from 175.28 ml. plus or minus standard deviation 36.053 to 216.71 plus or minus standard deviation 86.91. The 2 patients with stable increase of bladder capacity reported significant clinical improvement of frequency, nocturia and incontinence 4 weeks later.

Conclusions

Our results suggest that in humans there may be substantial differences in urodynamic effects between resiniferatoxin and capsaicin when the drugs are instilled into the bladder. Further studies, in vitro and in vivo, are necessary to define the pharmacological and clinical effects of resiniferatoxin. Because resiniferatoxin did not produce warm or burning sensations at the suprapubic/urethral level during infusion and seems to have rapid desensitization, it could be an interesting alternative to intravesical capsaicin in the treatment of select cases of bladder hyperactivity.     

ABOLITION OF CYSTITIS-INDUCED BLADDER INSTABILITY BY LOCAL SPINAL CORD COOLING

Purpose

The efficacy of lumbosacral spinal cord cooling for the suppression of reflex urinary incontinence was evaluated in a rat model of cystitis-induced bladder instability.

Materials and Methods

In female Sprague-Dawley rats, overactivity of the detrusor muscle was induced by inflammation of the urinary bladder. Isovolumetric intravesical pressure, urethral perfusion pressure and electromyographic (EMG) activity of the external urethral sphincter (EUS) were recorded simultaneously during repetitive local cooling (-2C or +15C) and rewarming (to 37C) of the dorsal L6/S1 spinal cord segments.

Results

Mustard oil-induced inflammation led to a marked instability of the urinary bladder without affecting urethral outlet functions. Local cooling of the dorsal lumbosacral spinal cord with temperatures of −2C as well as +15C completely abolished bladder voiding contractions in rats with an inflamed bladder as well as in non-inflamed control animals. Cooling had little effect on the EMG activity of the EUS and increased the urethral perfusion pressure. The suppression of detrusor reflex contractions was reversed within 1-7 min. after rewarming of the spinal cord.

Conclusions

Cooling of the dorsal spinal cord at the origin of the parasympathetic innervation of the bladder can be used for a reversible suppression of bladder instability without affecting the urethral outlet. Thus, local spinal cord cooling may offer a suitable method to restore continence in cases of reflex incontinence.     

INTRAVESICAL ELECTROMOTIVE DRUG ADMINISTRATION TECHNIQUE: PRELIMINARY RESULTS AND SIDE EFFECTS

Purpose

We performed intravesical electromotive drug administration (EMDA) for various bladder disorders during a 3-year period and assessed the technique, possible applications, complications and outcomes of this procedure.

Materials and Methods

Intravesical EMDA was performed with local anesthetics for transurethral surgery and in combination with dexamethasone for the treatment of noninfectious chronic cystitis (interstitial/radiation cystitis), with mitomycin C for recurrence prophylaxis of high risk superficial bladder cancer and with oxybutynin/bethanechol for the hyperreflexive/acontractile detrusor. A standardized power source and electrode catheter were used for 215 treatments in 84 patients.

Results

Transurethral bladder tumor resections were pain-free in 10 of 12 patients. Of the 25 patients with chronic noninfectious cystitis 15 were free of symptoms for a mean of 6.6 months, and there was a 73% increase in mean bladder capacity from 244 before to 421 cc after EMDA. Of the 16 patients with superficial bladder cancer 9 were free of recurrence for a mean of 14.1 months. In 10 of 14 patients with acontractile detrusors urodynamic examination showed detrusor contraction during EMDA of bethanechol. There were no contractions without electric current. EMDA of oxybutynin reduced detrusor hyperreflexia. A bladder ulcer was the single severe local complication and 4.6% of patients, mainly those with chronic cystitis, reported significant post-EMDA bladder/urethral pain. Minor side effects accounted for 23% of all treatments. No systemic side effects occurred.

Conclusions

Intravesical EMDA is effective and innocuous. The therapeutic concept combines the advantages of increased drug administration without systemic side effects.     

Reactive oxygen species mediate detrusor overactivity via sensitization of afferent pathway in the bladder of anaesthetized rats

OBJECTIVES

To investigate the effects of reactive oxygen species (ROS) on the micturition reflex in vivo, especially in bladder afferent signalling in rats, as several pathophysiological conditions in the urinary bladder (e.g. ischaemia/reperfusion and inflammation) are characterized by the formation of ROS.

MATERIALS AND METHODS

Adult female Sprague‐Dawley rats under urethane anaesthesia (normal or pretreated with 125 mg/kg capsaicin, subcutaneously, 4 days before) were assessed by continuous cystometrography (CMG) with or without the intravesical administration of H₂O₂ (0.003–3%) to stimulate ROS damage. To investigate the mechanism of H₂O₂, catalase (a H₂O₂ scavenger) was applied intravesically (2000 IU/mL), or rats were given intravenous injections with superoxide dismutase (SOD, 20 000 IU/kg, a superoxide anion scavenger), dimethylthiourea (DMTU, 100 mg/kg, a hydroxyl radical scavenger), deferoxamine (20 mg/kg, an iron‐chelator that prevents the formation of hydroxyl radical), indomethacin (3 mg/kg, a cyclooxygenase inhibitor) or ketoprofen (1 mg/kg, a cyclooxygenase inhibitor) just before or during the intravesical administration of H₂O₂. Prostaglandin (PG) levels (PGE₂ and 6‐keto‐PGF_1α) were measured in the bladder of rats treated with intravesical 0.3% H₂O₂ for 30 min with or without indomethacin.

RESULTS

Intravesical administration of H₂O₂ induced detrusor overactivity, as shown by a reduction in the mean (sem ) intercontraction interval (ICI), in a dose‐dependent manner in normal rats (0.3% H₂O_2, P < 0.01, 36.2 (4.7)% of the control ICI). H₂O₂‐induced detrusor overactivity was almost abolished by catalase and significantly suppressed by DMTU, deferoxamine, capsaicin pretreatment, indomethacin or ketoprofen but not by SOD. The level of PGs was significantly increased by H₂O₂ instillation, and indomethacin significantly inhibited the increase in PGs.

CONCLUSION

These results indicate that oxidative stress induced by H₂O₂ activates capsaicin‐sensitive C‐fibre afferent pathways, at least in part, mediated via stimulation of the cyclooxygenase pathway, thereby inducing detrusor overactivity. Thus, rats treated with intravesical H₂O₂ appear to be a suitable model for the study of detrusor overactivity.     

Der Stellenwert der intravesikalen Elektrostimulation in der Therapie der akuten prolongierten Blasenüberdehnung

Background

The effectiveness of intravesical electrostimulation (IVES) in the treatment of acute prolonged bladder overdistension (PBO) was investigated.

Methods

Sixteen patients (♀11, ♂5, ø54 years) after PBO (bladder filling volume: 1317±320 ml) were evaluated: 11 after surgery and 5 after polytrauma, psychosomatic disorder or LV4 fracture. After exclusion of a neurogenic aetiology and a urodynamic examination, IVES was performed besides IC or suprapubic catheter.

Results

Group 1: six patients with a weak detrusor (p_{detr. max.}<30 cmH₂O); group 2: ten patients had detrusor acontractility. After 25 IVES sessions, group 1 showed a significant increase of p_{detr. max.} (p=0.01) as well as a decrease in PVR (31% to 3% of bladder capacity, p=0.02). Group 2 had no significant increase of p_{detr. max}.

Conclusions

Two-thirds of patients with a weak detrusor after PBO will regain balanced voiding after IVES due to detrusor reinforcement. With an acontractile detrusor only bladder sensation improves.     

Reduction of intercellular adhesion molecule 1 may play a role in anti-inflammatory effect of hyaluronic acid in a rat model of severe non-bacterial cystitis

Purpose

To evaluate the impact of intercellular adhesion molecule 1 (ICAM-1) in hyaluronic acid (HA) therapy in rats model of severe non-bacterial cystitis.

Methods

Cystitis models in Sprague–Dawley female rats were produced by combination of intraperitoneal cyclophosphamide (CYP) with intravesical protamine/lipopolysaccharide (PS/LPS). HA or heparin (0.5 ml) was introduced intravesically to rats’ bladders followed PS/LPS. Bladder tissue was prepared for histology including mast cell presence and measurement of ICAM-1, tumor necrosis factor (TNF)-α, and interleukin 6 (IL-6).

Results

Cystitis model using intraperitoneal CYP and intravesical SP/LPS showed serious inflammation, higher mast cell count with elevated ICAM-1, TNF-α, and IL-6 levels. After intravesical heparin or HA treatment, incidence of grades 3–4 bladder inflammation and tissue ICAM-1 level were only significantly lower in HA group (P = 0.017, P = 0.021, respectively), but not in heparin group (P = 0.12, P = 0.798, respectively). Remarkably lower level of TNF-α (P = 0.003) and ICAM-1 (P = 0.006) was detected in HA-treated rats compared with heparin-treated rats. Inflammation grade and ICAM-1 level had strong correlation (P < 0.001). IL-6 level after HA or heparin instillation had no difference.

Conclusions

Intravesical administration of HA decreased the severity of bladder inflammation, mast cell presence, and levels of ICAM-1 and TNF-α in a rat model of severe non-bacterial cystitis; its effect was more obvious than that of heparin. Reduction of ICAM-1 may play a role in the anti-inflammatory effect of HA.     

Effects of the gonadotropin-releasing hormone antagonist ganirelix on normal micturition and prostaglandin E(2)-induced detrusor overactivity in conscious female rats

Background

Gonadotropin-releasing hormone (GnRH) antagonists have been reported to have beneficial effects on lower urinary tract symptoms in patients with benign prostatic hyperplasia.

Objective

Our aim was to investigate the effects of ganirelix, a GnRH receptor antagonist, on bladder function and detrusor overactivity (DO) in female rats.

Design, setting, and participants

Female Sprague-Dawley rats received 2 wk of daily systemic (0.1 mg/kg) or acute intravesical administration (IVES; 0.14 mg/l or 1.4 mg/l) ganirelix or vehicle (controls).

Measurements

Assessments were obtained using cystometry in awake rats, organ bath studies, enzyme-linked immunosorbent assay, and western blot (WB).

Results and limitations

Luteinising hormone levels were lower in rats treated systemically with ganirelix than in controls. No differences were observed in body or bladder weights. Micturition interval (MI), micturition volume (MV), residual volume, and bladder capacity (BC) were similar in both groups at baseline. No differences in urodynamic pressure parameters were observed between groups at baseline. Intravesical prostaglandin E₂ reduced MI, MV, and BC, and it increased basal pressure (BP), threshold pressure (TP), flow pressure (FP), and maximum pressure (MP) in all rats. MI, MV, and BC were reduced by 43% ± 4%, 50% ± 4%, and 43% ± 4% (controls) versus 22% ± 3%, 23% ± 3%, and 21% ± 3% (ganirelix-treated rats; p < 0.001). TP and FP increased by 38% ± 8% and 30% ± 4% (controls) versus 16% ± 7% and 16% ± 5% (ganirelix; p < 0.05). The maximal force of contractions for carbachol was larger in detrusor from ganirelix-treated rats (231% vs 177% of 60 mM K+-induced contractions). At 0.14 mg/l, but not 0.14 mg/l, IVES ganirelix increased MI, MV, and BC and decreased BP, TP, FP, and MP. In vitro, ganirelix had no effect on detrusor function. The gonadotropin-releasing hormone receptor was expressed (by WB) in the bladder mucosa.

Conclusions

Systemic treatment with ganirelix counteracted experimental DO in female rats. Because bladder preparations from these rats exhibited larger contractions to carbachol and because intravesical ganirelix affected both micturition intervals and urodynamic pressure profiles, a peripheral site of action of ganirelix in the urinary bladder cannot be excluded.     

Intravesical Morphine Analgesia after Bladder Surgery

Purpose

A recent demonstration of peripheral opioid receptors suggested the possibility of delivering morphine locally into the bladder after reimplantation for ameliorating the discomfort of postoperative bladder irritation with spasms. Since we do not use bladder drainage after reimplantation, dripping a morphine solution into the bladder permits contact with the urothelium between voidings. A pilot trial using an arbitrary concentration was subjectively beneficial for treating these patients postoperatively. We now report a prospective randomized study evaluating the effectiveness and dosage of various concentrations of intravesical morphine infusions.

Materials and Methods

A total of 52 children undergoing ureteral reimplantation was randomized to receive 1 of 3 concentrations of intravesical morphine (0.05, 0.375 or 0.5 mg./ml.). A small feeding tube remained in the bladder to drip a continuous infusion postoperatively. Subsequent postoperative pain was treated with meperidine, acetaminophen and codeine, and/or a belladonna and opium suppository. During each shift a nurse assisted the child in assessing pain using a Baker-Wong faces scale. Bladder infusion was discontinued after day 3 postoperatively and plasma morphine levels were measured on the first morning postoperatively. Kruskal-Wallis and paired t tests were used to evaluate significance.

Results

Patients reported greater pain in the group infused with 0.05 mg./ml. on 4 of 6 shifts on the first 2 days postoperatively. No difference was noted on postoperative day 3. Plasma morphine was undetectable by high pressure liquid chromatography.

Conclusions

This study offers objective evidence that bladder morphine infusion is effective for ameliorating postoperative pain in the first 48 hours after intravesical ureteral reimplantation. The dose given today is 0.5 mg./ml. delivered at 0.04 ml./kg. per hour.     

INTRAVESICAL OXYBUTYNIN: MODE OF ACTION ASSESSED BY PASSIVE DIFFUSION AND ELECTROMOTIVE ADMINISTRATION WITH PHARMACOKINETICS OF OXYBUTYNIN AND N-DESETHYL OXYBUTYNIN

PURPOSE: A proportion of patients with detrusor hyperreflexia who are unresponsive to oral oxybutynin often benefit from intravesical oxybutynin instillation. To our knowledge the precise mode of action of this method is obscure. MATERIALS AND METHODS: In 12 patients with detrusor hyperreflexia who were previously unresponsive to oral and intravesical passive diffusion of 5 mg. oxybutynin we administered 5 mg. oxybutynin orally as well as increased doses of 15 mg. oxybutynin intravesically with passive diffusion and with 15 mA. associated electric current. Each administration mode per patient was associated with an 8-hour urodynamic monitoring session during which oxybutynin and N-desethyl oxybutynin plasma levels, and intravesical oxybutynin uptake were measured. RESULTS: A dose of 5 mg. oxybutynin orally induced no urodynamic improvement with an area under the plasma concentration time curve of combined N-desethyl oxybutynin plus oxybutynin of 16,297 ng./8 hours and an area under the curve ratio of N-desethyl oxybutynin-to-oxybutynin of 11:1. Passive diffusion oxybutynin resulted in 12 mg. oxybutynin intravesical uptake and significant improvement in 3 of 8 urodynamic measurements, although the area under the curve of combined N-desethyl oxybutynin plus oxybutynin was only 2,123 ng./8 hours and the N-desethyl oxybutynin-to-oxybutynin ratio was 1.1:1.0. Electromotive administration of oxybutynin resulted in almost complete intravesical uptake of the 15 mg. dose, significant improvement in all 8 urodynamic measurements and an increased oxybutynin level versus oral and passive diffusion, although the area under the curve of combined N-desethyl oxybutynin plus oxybutynin was 4,574 ng./8 hours and the N-desethyl oxybutynin-to-oxybutynin ratio was inverted at 1.0:1.4. The oral dose of 5 mg. oxybutynin caused anticholinergic side effects in 8 of the 12 patients. Neither intravesical passive diffusion nor electromotive administration caused side effects with an uptake of 12 and 15 mg., respectively. CONCLUSIONS: A large proportion of intravesical oxybutynin is sequestered, probably in the urothelium. Intravesical oxybutynin administration confers therapeutic benefits via localized direct action within the bladder wall.     

Urodynamic Evaluation in Simultaneous Insulin-Dependent Diabetes Mellitus and End Stage Renal Disease

Purpose

We evaluated the urodynamic changes produced by insulin-dependent diabetes mellitus with end stage renal disease.

Materials and Methods

A urodynamic evaluation was performed on 51 young patients (mean age plus or minus standard deviation 35 plus/minus 6 years) with long-term diabetes mellitus (average 21 plus/minus 6 years) and end stage renal disease (86 percent on dialysis).

Results

The urodynamic study was abnormal in 84 percent of the patients. The bladder was hypersensitive in 39 percent and hyposensitive in 30 percent of the cases, and maximum vesical capacity was greater than 600 ml. in 33 percent. An acontractile detrusor was noted in 6 percent of the patients, while 4 percent had detrusor hyperreflexia and 35 percent had bladder outlet obstruction.

Conclusions

A high frequency of vesical alterations was observed, which were modified by association of progressive vesical dysfunction and diabetes mellitus. In diabetes mellitus dialysis protects against detrusor hypocontractility but predisposes the patients to have bladder obstruction.     

THE ROLE OF URINARY POTASSIUM IN THE PATHOGENESIS AND DIAGNOSIS OF INTERSTITIAL CYSTITIS

Purpose

We determined whether intravesical potassium absorption in normal bladders correlates with increased sensory urgency, and corroborated the hypothesis that mucus is important in the regulation of epithelial permeability. We compared sensory nerve provocative ability of sodium versus potassium, and determined whether intravesical potassium sensitivity discriminates patients with interstitial cystitis from normal subjects and those with other sensory disorders of the bladder.

Materials and Methods

A total of 231 patients with interstitial cystitis and 41 normal subjects underwent intravesical challenge with 40 ml. water and then 40 ml. of 40 mEq./100 ml. potassium chloride. Subjective responses of urgency or pain stimulation were recorded on a scale of 0 to 5. In 19 normal subjects potassium absorption was measured at baseline, after injury of the bladder mucus with protamine, after heparin treatment to reverse mucus damage and then for a final time. These subjects simultaneously recorded the symptoms of sensory urgency and pain at baseline, after protamine and after heparin. Another group of normal volunteers underwent a challenge with sodium versus potassium to determine which cation was more provocative. Patients with bladder outlet obstruction secondary to benign prostatic hyperplasia (BPH), detrusor instability, and acute and chronic urinary tract infection but no current infection were also evaluated for potassium sensitivity.

Results

Neither normal subjects nor patients with interstitial cystitis reacted to water administered intravesically. There was marked sensitivity to intravesical potassium in 75% of patients with interstitial cystitis versus 4% of controls (p <0.01). Only 1 patient with BPH responded to potassium and none of the 5 with chronic urinary tract infection responded. All 4 patients (100%) with a current acute urinary tract infection reacted positively to the potassium challenge. Of 16 patients with detrusor instability 25% responded. Normal subjects had minimal sensitivity to potassium before (11%) and markedly increased sensitivity after (79%) protamine treatment, and these symptoms were reversed by heparin in 42%. Potassium absorption directly correlated with symptoms (0.4, 3.0 and 1.3 mEq. before and after protamine, and after heparin reversal, respectively). In regard to sodium versus potassium provocation, potassium was far more provocative for causing urgency after protamine (10 versus 90%). Neither group underwent provocation before protamine.

Conclusions

Chronic diffusion of urinary potassium into the bladder interstitium may induce sensory symptoms, damage tissue and be a major toxic factor in the pathogenesis of interstitial cystitis. Intravesical potassium sensitivity is a reliable method for detecting abnormal epithelial permeability. It discriminates between patients with interstitial cystitis and normal subjects with intact epithelial function, and it is a useful diagnostic test for interstitial cystitis. Potassium sensitivity correlates with increased potassium absorption in normal subjects, and potassium is far more provocative than sodium. Potassium sensitivity is also present in acute urinary tract infection and occasionally detrusor instability but not in BPH or chronic urinary tract infections.