Doi:10.1016/j.eururo.2003.11.006

European Urology 45 (2004) 516–520 Oral Nitric Oxide Donors: A New PharmacologicalApproach to Detrusor-Sphincter Dyssynergia inSpinal Cord Injured Patients? Andre´ Reitz, Peter A. Michael Mu¨ntenerBrigitte SchurchaNeuro-Urology, Swiss Paraplegic Center, Balgrist University Hospital, Forchstrasse 340, 8008 Zurich, SwitzerlandbDepartment of Urology, University Hospital, Zurich, Switzerland Accepted 4 November 2003 Published online 26 November 2003 AbstractPurpose: Detrusor-sphincter dyssynergia is a common cause of bladder outlet obstruction in spinal cord injuredpatients and leads to poor bladder emptying and high bladder pressures, which if left untreated might cause renalfailure. In this study, we tested the recently published hypothesis that oral administration of a nitric oxide donorcould be a new pharmacological approach to treat detrusor-sphincter dyssynergia in humans with spinal cordinjury.
Methods: 12 male spinal cord injured patients presenting with neurogenic detrusor overactivity and detrusor-sphincter dyssynergia were studied. 6 performed clean intermittent catheterisation and 6 used suprapubic tappingfor bladder emptying. During cystometry the bladder was filled until the first overactive bladder contractionaccompanied by detrusor-sphincter dyssynergia occurred while bladder and external urethral sphincter pressureswere continuously recorded. Then the bladder was emptied and the patients received 10 mg of isosorbidedinitrate sublingually. Resting pressures were recorded and cystometry was repeated starting 15 min after drugadministration. Maximal and mean values for bladder and external urethral sphincter pressures were calculated inboth fillings and statistically compared by analysis of variance for repeated measurements (level of significancep < 0:05).
Results: Nitric oxide significantly reduced external urethral sphincter pressures at rest ( p < 0:05) and duringdyssynergic contraction ( p < 0:05) while bladder pressures at rest and during contraction as well as the reflexvolume remained unchanged. In the patients who used suprapubic tapping for bladder emptying the mean posttriggering residual volume was significantly reduced ( p < 0:05).
Conclusions: Oral administration of nitric oxide donors significantly reduced bladder outlet obstruction due todetrusor-sphincter dyssynergia suggesting a role for nitric oxide in inhibitory neurotransmission to the urethralsphincter. This new approach could offer a potential pharmacological option to treat detrusor-sphincter dyssynergiain spinal cord injured patients.
# 2003 Elsevier B.V. All rights reserved.
Keywords: Spinal cord injury; Bladder; Neurogenic bladder; Neurotransmitters; Nitric oxide and urethral sphincter function. This phenomenonknown as detrusor-sphincter dyssynergia (DSD) is Patients with spinal cord injuries (SCI) on suprasa- defined as the presence of an involuntary contraction cral level often lose the coordination between bladder of the external urethral sphincter during an involuntarydetrusor contraction DSD is a common cause of bladder outlet obstruction in this patient population Corresponding author. Tel. þ41-1-386-3721; Fax: þ41-1386-3731.
E-mail address: areitz@balgrist.unizh.ch (A. Reitz).
and leads to several complications which increase 0302-2838/$ – see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2003.11.006 A. Reitz et al. / European Urology 45 (2004) 516–520 morbidity after SCI. Poor bladder emptying and high suprasacral SCI. Furthermore, the post-triggering resi- bladder pressures can cause recurrent urinary tract dual volume in 6 patients using suprapubic tapping for infections, structural bladder damage and vesicoure- bladder emptying were compared with vs. without nitric teric reflux, which ultimately may lead to hydrone- phrosis and renal failure.
Treatment options include reversible interventions such as the injection of botulinum toxin into the 2. Patients and methods external urethral sphincter, balloon dilatation of thesphincter, implantation of urethral stents or the external 12 male patients (mean age 32 years, range 29–36) with chronic sphincterotomy. Basically, all these procedures are suprasacral spinal cord injury were studied. All patients presented more or less effective but have considerable side with upper motor neuron lesion, neurogenic detrusor overactivityand DSD. Medication known to influence the vesicourethral func- effects. Urethral stents are prone to incrustation and tion was discontinued within 48 h before the test and none of the stone formation. The botulinum toxin injections need patients had used sildenafil for treatment of erectile dysfunction to be repeated within intervals of 2–4 months. Also the during that period. Patients with higher thoracic or cervical lesions results of surgical sphincterotomy are not fully con- and known severe hypotonia were excluded.
vincing. Prospective studies showed that in 15–40% Patients underwent detailed neurological examination to confirm repeated sphincterotomy is required and raised residual the segmental level of SCI. 6 patients performed clean intermittentcatheterisation and 6 used triggered voiding for bladder emptying.
urine volumes and recurrent urinary tract infections During standard cystometry with saline solution of room tempera- persisted in 20–35% and 20–25% respectively ture the pressures within the bladder and the external urethral Reflux failed to resolve in 10–60% and hydronephrosis sphincter (EUS) were continuously recorded using an 8 French remained in around 30%. In patients with cervical and three channel pressure transducer catheter (Unisensor, Switzer- higher thoracic lesions bladder filling associated auto- land). Correct placement of the pressure transducers within thebladder and the EUS was ensured radiologically using fluoroscopy.
nomic dysregulation persisted in 5–10% after sphinc- The abdominal pressure was measured using an 8 F single channel terotomy Although severe surgical complications pressure transducer catheter placed in the rectum.
are rare, urethral strictures in 5–10% and erectile During baseline cystometry the bladder was filled with 10 ml per dysfunction in 3–7% needs to be considered. Further- second until the first bladder contraction accompanied by DSD more, the main goal of the procedure, to decrease high occurred. The volume infused is defined as reflex volume. Patientswho used triggered voiding as standard bladder management then intravesical pressures as a potential risk factor for renal emptied their bladder by repeated suprapubic triggering until the damage, can not be achieved in a considerable number urine flow stopped. Afterwards, the bladder was emptied by of patients and around one third of the patients develop catheterisation and the residual urine was measured.
upper urinary tract complications. To sum up it can be All patients received 10 mg of isosorbide nitrate sublingually said that effective, reversible and well-tolerated treat- while heart rate and blood pressure were monitored continuously.
ment strategies for DSD in SCI men are currently not To study the drug effect on the resting bladder and EUS activityboth pressures were continuously recorded five minutes before and within the first 15 minutes after drug delivery. For that period Since alpha-blockers are often not effective in detru- bladder and EUS pressures were analyzed and mean values were sor-sphincter dyssynergia a short and locally calculated within four time windows (baseline, 0–5 min, 5–10 min, acting pharmacological agent such as a nitric oxide 10–15 min).
donor could be the solution in this group of patients.
Afterwards standard cystometry was repeated starting 15 min after drug delivery up to the point, when the first bladder contrac- Recently Mamas et al. hypothesized that nitric oxide tion accompanied by DSD occurred. In patients on triggered donors could be a potential new treatment option for voiding the post-triggering residual volume was measured again detrusor-external urethral sphincter-dyssynergia by catheterisation. The obtained pressure curves for both fillings Animal and human studies suggested that the inhibi- were recorded with a 1000 Hz sampling rate and further analyzed tory neurotransmitter nitric oxide plays an important using the SoleasyTM-software package (ALEASolutions, Switzer-land). Mean values for bladder and EUS pressures at baseline regulatory role in urethral sphincter relaxation . In before bladder contraction and within time frames of 30, 60, 90 and this study, we hypothesized that the oral administration 120 sec after onset of an uninhibited bladder contraction were of nitric oxide donors first could lower the resting calculated in both fillings and compared by analysis of variance for external urethral sphincter pressure; second could lower repeated measures (level of significance p < 0:05).
the sphincter pressure during dyssynergic sphinctercontraction, and third could reduce the maximal bladderpressure during voiding. Within an acute urodynamic study the effect of the oral nitric oxide donor isosorbidenitrate on dyssynergic external urethral sphincter activ- Cystometry and drug treatment were well tolerated ity and voiding pressure was assessed in 12 males with in all patients. In 7 patients mild headache occurred.
A. Reitz et al. / European Urology 45 (2004) 516–520 time (sec)
Fig. 3. Resting bladder pressures separately calculated as mean value for Fig. 1. Neurogenic detrusor overactivity accompanied by DSD in a patient every single patient within the time frames of 5 min duration before and with traumatic SCI on T6 level (EUS: external urethral sphincter, BLA: after sublingual administration of 10 mg isosorbide dinitrate.
Nitric oxide lowered the mean blood pressure from 10 min and 20.6 cmH2O (S.D. 12.4) from 10 to 15 min.
124/85 mmHg to 102/68 mmHg and increased heart rate from 72 beats per min to 96 beats per minute. This Then cystometry was repeated and in all patients an cardiovascular effect lasted for a period up to 30 min and was without any clinical significance.
(). The mean reflex volume was 369 ml ranging During baseline cystometry all patients studied from 201 ml to 458 ml (non significant vs. baseline showed an uninhibited bladder contraction accompa- reflex volume) and the mean voiding pressure was nied by DSD (). The mean reflex volume was 62.4 cmH2O (S.D. 21.9) which was non significant 345 ml (range 194–456 ml) and the mean voiding from the baseline voiding pressure. In the six patients pressure was 65.8 cmH2O (S.D. 23.0). Post-triggering who used to empty their bladder by suprapubic trigger- residual urine volume in the group of 6 patients using ing the post-triggering residual volume was with 73 ml suprapubic triggering for bladder emptying was 133 ml(S.D. 47).
Following sublingual administration of 10 mg iso- sorbide dinitrate the EUS pressure decreased in all individuals studied. The mean EUS resting pressure decreased significantly from 74.9 cmH2O (S.D. 22.5) at baseline to 63.4 cmH 2O (S.D. 20.8, p < 0:05) cal- culated from 0 to 5 min, to 48.4 cmH p < 0:05) calculated from 5 to 10 min and to 42.4 cmH2O (S.D. 18.5, p < 0:05) calculated from 10 to 15 min In the same period the mean time (sec)
resting bladder pressure remained almost unchanged Fig. 4. Neurogenic detrusor overactivity accompanied by DSD in the same (16.1 cmH2O (S.D. 6.9) at baseline, 15.1 cmH2O (S.D.
patient as shown in , 20 min after sublingual administration of 10 mg 6.8) from 0 to 5 min, 17.8 cmH 2O (S.D. 9.5) from 5 to mean p EUS baselinemean p EUS with NO Fig. 2. Resting external urethral sphincter pressures separately calculatedas mean value for every single patient within the time frames of 5 min Fig. 5. Mean external urethral sphincter pressures (mean  S:D:) during duration before and after sublingual administration of 10 mg isosorbide dyssynergic external sphincter contractions before and after sublingual administration of 10 mg isosorbide dinitrate (n ¼ 12).
A. Reitz et al. / European Urology 45 (2004) 516–520 mean p bladder baseline contracts. This leads to high bladder pressures and mean p bladder with NO elevated residual urine, structural bladder damage and vesicoureteral reflux, and when combined with recurrent infections to renal failure. To date, treatment options for detrusor-sphincter dyssynergia are limited and in many patients ineffective. Therefore, new approaches to this unsolved problem are necessary.
In the present acute urodynamic study we found that sublingual nitric oxide donors lower the EUS pressure at rest and during contraction. After sublingual admin- istration isosorbide dinitrate reaches maximal plasma Fig. 6. Mean bladder pressures (mean  S:D:) during neurogenic detrusor concentrations after 10–15 min and the duration of the overactivity and dyssynergic external sphincter contractions before andafter sublingual administration of 10 mg isosorbide dinitrate (n ¼ 12).
effect is estimated to be 1–2 hours (half-life 30–40 min). The EUS is considered to have a rich bloodsupply. Therefore, after sublingual administration the (S.D. 35) significantly lower than without isosorbide drug should reach the sphincteric area within a few dinitrate ( p < 0:05).
minutes. This consideration corresponds with our find- Mean value calculations within the analyzed time ings during the first 15 min after drug administration windows of 30 s, 60 s, 90 s and 120 s after the onset of when we observed the resting EUS pressure. Already an uninhibited bladder contraction revealed that the after 5 min there was a significant decrease of the nitric oxide donor significantly decreased the EUS resting sphincter pressure which decreased further after pressure ( p < 0:05) without having a significant effect 10 and 15 minutes. These findings suggest that sub- in bladder pressure ().
lingually administered nitric oxide donors can lowerthe resting pressure of the EUS significantly within ashort period of time and maintain this reduction for at least more than 15 min.
Also the contractile ability of the EUS seems to be To our knowledge, this is the first study using an oral influenced by the drug. Mean EUS pressures calculated nitric oxide donor as a pharmacological approach to within time frames of 30, 60, 90 and 120 s after onset of DSD in spinal cord injured patients. In this urodynamic a overactive bladder contraction were significantly controlled study the oral administration of 10 mg iso- lower with isosorbide dinitrate than without. This sug- sorbide dinitrate significantly reduced EUS pressure at gests that sublingual administration of isosorbide dini- rest and also during dyssynergic sphincter contraction.
trate results in a significant reduction of the contractile Furthermore, the drug treatment improved bladder strength of the EUS during a dyssynergic contraction.
emptying in patients who used to empty their bladder Since high volumes of residual urine might increase the by suprapubic tapping and reduced the post-void resi- risk of urinary tract infections and bladder stones, a dual volume significantly.
more or less complete bladder emptying is crucial in Nitric oxide has been suggested as an important patients using suprapubic tapping for voiding. Our inhibitory neurotransmitter in the lower urinary tract.
results show that the post-triggering residual volume Nerves with the capacity to synthesize nitric oxide in these patients is significantly lower with nitric oxide supply the urethra and the urinary bladder and indicating an improved bladder emptying by a reduction those nerves seem to be predominant in the parasym- of the bladder outlet obstruction caused by DSD.
pathetic innervation of the urethra . Nitric oxide Concerning our third hypothesis, the drug did not also seems to be important for the relaxation of the influence the resting bladder pressure and it did not striated external urethral sphincter significantly reduce the mean bladder pressure during After spinal cord injury on a suprasacral level the contraction. This supports earlier findings that nitrergic coordination between detrusor and sphincter is fre- innervation within the bladder is sparse. However, the quently absent because the inhibitory pathways from main goal of a new treatment option would be a the brain stem to the sacral spinal cord and the urethral reduction of high voiding pressures which cause the sphincter structures are disrupted. The lack of suprasp- unfavourable consequences such as bladder wall inal coordination of bladder and sphincter function damage, reflux and renal failure. A possible explana- causes poor bladder emptying because when the blad- tion for the persisting high bladder pressure during der contracts the sphincter does not relax or even also voiding despite considerable reduced outlet resistance A. Reitz et al. / European Urology 45 (2004) 516–520 is an adaptation of the detrusor muscle on a certain disappear when the drug is used for longer times.
contractile strength which cannot be changed during an Further studies are required to evaluate the efficacy acute experiment, but might improve after chronic and safety of a chronic administration of oral nitric administration. However, in patients using suprapubic oxide donors to treat DSD in SCI patients.
tapping for bladder emptying a sufficient bladdercontractility should be maintained to ensure voidingwith tolerable residual urine volumes.
Since nitric oxide donors can cause hypotonia and tachycardia, cardiovascular monitoring is recom- Oral administration of nitric oxide donors signifi- mended especially in patients with spinal cord injury cantly reduced bladder outlet obstruction due to DSD on the level T6 and higher because they are known to in the spinal cord injured patients studied, and have hypotonia frequently at rest. Autonomic dysre- improved bladder emptying in the patients with trig- gulation in response to bladder filling or contraction is gered voiding. These results are consistent with a role also common in theses patients and nitric oxide donors for nitric oxide in inhibitory neurotransmission to the could provide in addition to the sphincter relaxation a urethral sphincter. This pharmacological approach beneficial cardiovascular effect and avoid excessive could offer a potential new treatment option for bladder blood pressure rise and bradycardia.
outlet obstruction due to DSD.
Because of the risk of severe hypotension the parallel intake of sildenafil must be avoided and a carefulhistory is necessary prior to treatment since many of spinal cord injured men take sildenafil for erectiledysfunction. In 7 of the 12 studied patients headache The authors are grateful to Mr. H. van Hedel for has been observed after drug administration, which is a statistical assistance. This study was supported by the typical side effect of nitric oxide donors but known to Swiss National Foundation (Grant No. 32.52562.97).
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