Bladder pain induced by prolonged peripheral alpha 1A adrenoceptor stimulation involves the enhancement of transient receptor potential vanilloid 1 activity and an increase of urothelial adenosine triphosphate release.

AIM: Pathophysiological mechanisms of chronic visceral pain (CVP) are unknown. This study explores the association between the sympathetic system and bladder nociceptors activity by testing the effect of a prolonged adrenergic stimulation on transient receptor potential vanilloid 1 (TRPV1) activity and on urothelial adenosine triphosphate (ATP) release. METHODS: Female Wistar rats received saline, phenylephrine (PHE), PHE + silodosin, PHE + naftopidil or PHE + prazosin. TRPV1 knockout and wild-type mice received saline or PHE. Visceral pain behaviour tests were performed before and after treatment. Cystometry was performed, during saline and capsaicin infusion. Fos immunoreactivity was assessed in L6 spinal cord segment. Human urothelial ATP release induced by mechanical and thermal stimulation was evaluated. RESULTS: Subcutaneous, but not intrathecal, PHE administration induced pain, which was reversed by silodosin, a selective alpha 1A adrenoceptor antagonist, but not by naftopidil, a relatively selective antagonist for alpha 1D adrenoceptor. Silodosin also reversed PHE-induced bladder hyperactivity and L6 spinal cord Fos expression. Thus, in subsequent experiments, only silodosin was used. Wild-type, but not TRPV1 knockout, mice exhibited phenylephrine-induced pain. Capsaicin induced a greater increase in voiding contractions in PHE-treated rats than in control animals, and silodosin reversed this effect. When treated with PHE, ATP release from human urothelial cells was enhanced either by mechanical stimulation or by lowering the thermal threshold of urothelial TRPV1, which becomes abnormally responsive at body temperature. CONCLUSION: This study suggests that the activation of peripheral alpha 1A adrenoceptors induces CVP, probably through its interaction with TRPV1 and ATP release.

Neurologic urinary incontinence.

INTRODUCTION: This manuscript summarizes the work of Committee 10 on neurologic bladder and bowel of the International Consultation on Incontinence in 2008-2009. As the data are very large the outcome is presented in different manuscripts. This manuscript deals with neurologic urinary incontinence. METHODS: Through in debt literature review all aspects of neurological urinary incontinence were studied for levels of evidence. Recommendations for diagnosis and treatment, and for future research were made. RESULTS: Pathophysiology was summarized for different levels of lesions. For epidemiology, specific diagnostics, conservative treatment and surgical treatment of neurologic urinary incontinence, levels of evidence and grades of recommendation were made following ICUD criteria. CONCLUSIONS: Though data are available that advice and guide in the management of urinary incontinence in neurologic patients, not many data have a high level of evidence or permit a high grade of recommendation. More and well-structured research is needed.

Neurologic fecal incontinence.

INTRODUCTION: This manuscript summarizes the work of Committee 10 on neurologic bladder and bowel of the International Consultation on Incontinence in 2008-2009. As the data are very large the outcome is presented in different manuscripts. This manuscript deals with neurologic fecal incontinence (FI). METHODS: Through in debt literature review all aspects of neurologic urinary and FI were studied for levels of evidence. Recommendations for diagnosis and treatment, and for future research were made. RESULTS: Pathophysiology was summarized for different levels of lesions. For epidemiology, specific diagnostics, conservative treatment, and surgical treatment of neurologic FI levels of evidence and grades of recommendation were made. CONCLUSIONS: Though data are available that advice and guide in the management of FI in neurologic patients, not many data are with a high level of evidence or high grade of recommendation. More and well-structured research is needed.

The role of capsaicin-sensitive afferents in autonomic dysreflexia in patients with spinal cord injury.

OBJECTIVES: To determine whether capsaicin-sensitive nerves in the bladder form the afferent limb involved in autonomic dysreflexia (AD) in patients with spinal cord injury (SCI). PATIENTS AND METHODS: Seven men with SCI (five cervical cord, two thoracic cord) with AD and detrusor hyper-reflexia (DH) were enrolled. Under general anaesthesia, capsaicin solution (100 mL of 2 mmol/L in 10% ethanol) was instilled in the bladder and retained for 30 min. The patients were assessed by medium-fill cystometry (CMG) just before and 50 min after the capsaicin treatment. Intra-arterial blood pressure (BP) and heart rate were monitored continuously throughout the procedure; 10% ethanol was instilled before capsaicin treatment in four patients as a control. Serum catecholamines were measured during bladder filling and capsaicin treatment, and the blood ethanol concentration also measured after instillation in all patients. The CMG with concomitant monitoring of BP and heart rate was repeated 1 week, 1, 3, 6, 12 and 24 months after instillation. In two patients the instillations were repeated 5 and 12 months after the first because of recurrence of DH. Urodynamic variables assessed were maximum cystometric capacity (MCC), maximum amplitude of uninhibited detrusor contraction (UICmax), the bladder capacity at 40 cmH2O detrusor pressure (Cdp40) and a systolic BP of> 140 mmHg or diastolic BP of> 90 mmHg (C(HT)). RESULTS: There was an increase in BP and a decrease in heart rate in all patients during bladder filling before capsaicin treatment. Instillation of capsaicin produced a significant increase in both systolic and diastolic BP and a significant decrease in heart rate. The maximum cardiovascular effects were at 5-10 min after instillation and gradually returned to baseline within 40 min. The vehicle had negligible effects on either BP or heart rate. After capsaicin treatment, the responses of BP and heart rate to bladder distension were significantly reduced. Both serum catecholamine values and the blood ethanol concentration remained within normal limits. The mean (range) follow-up after the first treatment was 15 (6-30) months. One month after treatment all seven patients became continent and their episodes of AD became negligible and well tolerable between catheterizations (for 3-4 h); the effects lasted for >or= 3 months in all. MCC was significantly increased at 4 weeks and 3 months, and UICmax significantly decreased at 4 weeks after treatment. Both mean Cdp40 and C(HT) increased 1 week, 1 and 3 months after treatment. Two patients received a second instillation, and have been continent with no symptomatic AD for 6 and 24 months. The remaining five patients have been continent with no symptomatic AD for 6-12 months. CONCLUSION: These results indicate that intravesical capsaicin, but not the vehicle, acutely triggers AD in patients with SCI, suggesting involvement of bladder capsaicin- sensitive afferents in AD in these patients. The results also suggest that intravesical capsaicin may be a promising therapy for both AD and DH in such patients. Further long-term follow-up studies are needed to evaluate the duration of its effect.

[Significance of PSA-density: analysis in PSA gray zone cases].

We studied the sensitivity and specificity of digital examination and prostate specific antigen (PSA) density to detect prostatic cancer in those patients whose PSA values are in a range of 4 to 10 ng/ml or in a gray zone. Sextant prostate biopsy revealed 14 cases (17.2%) of prostatic cancer out of 81 PSA gray zone cases. The sensitivity of digital examination was 38.5%, and the specificity was 73.0%. If we use 0.29 as a PSA density cut-off value, the sensitivity was 70.0%, and the specificity was 70.0%. At a PSA density cut off value of 0.22, we could obtain 90% sensitivity, which was considered applicable for detection of cancer in PSA gray zone cases.

The serous-lined tunnel principle for urinary reconstruction: a more rational method.

OBJECTIVE: To examine the feasibility of using the serous-lined-tunnel principle for orthotopic neobladder, continent cutaneous diversion and ureteric replacement by an intestinal segment. Patients and methods We created: (i) an orthotopic ileal neobladder using the serous-lined technique for antirefluxing ureteric implantation in 16 patients; (ii) a continent ileal pouch, adopting the principle for continent-valve construction and for ureteric implantation, in 10 patients (another patient with a failed continent valve underwent revision using an adaptation of this principle; and (iii) by applying the same principle an ileal ureter with a proximal antirefluxing mechanism was constructed in two patients (with lower ureteric cancer), and total replacement of the ureter by a tubular segment of the colon in association with a continent transverse colon pouch in one irradiated patient. RESULTS: In all, 52 ureters implanted into ileal neobladders or continent pouches functioned well, with neither obstruction nor reflux; 11 continent valves functioned well with no incontinence. Two patients with ileal ureters showed no ileo-ureteric reflux and had less hydronephrosis than before surgery. The tubularized ureter provided a unidirectional flow into the pouch. Conclusion Ureteric reimplantation and continent valve formation achieved by adopting the serous-lined tunnel principle provided satisfactory results. The versatility of the principle is apparent in the present experience and the creative application of the serous-lined tunnel principle should be possible in urinary reconstruction.

[Laparoscopic adrenalectomy at Shinshu University School of Medicine].

We report our experience with transperitoneal laparoscopic adrenalectomy in 26 cases (mean age 45 years). We experienced primary aldosteronism in 19 cases, Cushing syndrome in 6 cases and non-functioning tumor in one case. There was no significant difference in the operation time between right and left, men and women, primary aldosteronism and Cushing syndrome. The blood loss decreased with training. There were no severe complications during and after the operation. The weight of the resected adrenal glands increased. The blood loss decreased significantly compared with the open surgery. Transperitoneal laparoscopic adrenalectomy is becoming the safe and standard surgery for the adrenal gland tumor, and the number of suitable cases for this procedure is expected to increase in the future.

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.

Relaxant effects of isoproterenol and selective beta3-adrenoceptor agonists on normal, low compliant and hyperreflexic human bladders.

PURPOSE: We compared the relaxant effects of the stimulation of beta-adrenoceptors with isoproterenol and of drugs selective for beta-adrenoceptor subtypes in detrusor preparations from patients with normal and neurogenic bladder, respectively. MATERIALS AND METHODS: We studied in vitro preparations of a cystometrically normal, low compliant and hyperreflexic bladder from 45, 26 and 7 patients, respectively. RESULTS: Isoproterenol relaxed concentration dependently and with the same potency as detrusor preparations obtained from normal and neurogenic bladders. In 37 normal detrusor, 25 low compliant and 7 hyperreflexic cases pD2 values were 6.36, 6. 25 and 6.38, respectively. Maximal relaxation did not differ significantly among the 3 groups (about 80% of 10-5 M. forskolin induced relaxation). Neither the beta1-/beta2-adrenoceptor agonist dobutamine nor the beta2-adrenoceptor agonist procaterol produced any significant relaxation of preparations from the 3 groups at a concentration of up to 10-5 M. At a concentration of 10-4 M. the preparations were relaxed but neither of these effects reached a maximum. BRL37344A and CL316243, selective beta3-adrenoceptor agonists and CGP-12177A (a selective beta3-adrenoceptor partial agonist and beta1-/beta2-adrenoceptor antagonist) relaxed detrusor preparations from the normal, low compliant and hyperreflexic groups when applied at concentrations greater than 10-6 M. For each agonist the pD2 value did not differ significantly among the 3 groups. CONCLUSIONS: beta-adrenoceptor stimulation is an effective way of relaxing the human detrusor and the effect is similar in normal and neurogenic bladders. A major portion of the relaxant effect of isoproterenol is mediated via beta3-adrenoceptor stimulation. Clinical trials may reveal whether this method is useful for treating bladder overactivity.

A rat model for investigation of bladder dysfunction associated with demyelinating disease resembling multiple sclerosis.

Myelin basic protein (MBP) can be used as an antigen for inducing experimental allergic encephalomyelitis (EAE). In various studies, EAE animals have been used as an experimental model of demyelinating diseases. The aim of this study was to determine whether EAE, induced by MBP in rats, can be useful for investigation of bladder dysfunction associated with demyelinating disease. Female Lewis rats were used. In Study 1, the time course of behavioral and cystometric changes were observed consecutively after MBP sensitization. In Study 2, the correlations between behavioral, cystometric, and histologic abnormalities were studied. The degree of paralysis and histologic findings were evaluated. In Study 1, transient hind limb paralysis was observed in all rats. Cystometric findings were characterized by three different patterns: 1) detrusor areflexia (DA), 2) detrusor hyperactivity (DH), and 3) normal. Ten (77%) of the 13 rats given MBP showed bladder dysfunction, including DA (seven), DA/DH (two) and DH (one). Study 2 showed DA in 10 rats, DH in one, and normal findings in nine animals. The difference in degree of paralysis between the DA and the cystometrically normal animals was statistically significant (P<0.01). The mean value of the degree of inflammation in the spinal cord (L6-S1) in the DA group was significantly (P<0.05) higher than that in the cystometrically normal group. The degrees of paralysis and spinal inflammation were weakly correlated (R = 0.47, P = 0.05). The present rat model seems useful for studies of bladder dysfunction associated with spinal myelitis/demyelinating diseases.

Improvement of urological-management abilities in individuals with tetraplegia by reconstructive hand surgery.

OBJECTIVE: To evaluate whether reconstructive hand surgery could improve the ability of tetraplegic patients to perform clean intermittent self-catheterization (CIC). MATERIALS AND METHODS: The subjects were patients with complete traumatic tetraplegia admitted to the Nagano Rehabilitation Center between 1977 and 1996. A total of 63 subjects were included in this study with an age range of 18-73 years (mean 38.2 years). Reconstructive hand surgery was performed on 44 hands (28 cases). Current urological conditions were assessed by interview or mail questionnaire. RESULTS: Fifty-one per cent (22/43) of the patients with C6 level of tetraplegia and 86% (12/14) of those with C7 or C8 neurological level of injury could perform CIC independently and only one subject needed assisted CIC. CONCLUSION: CIC is the preferred option for people with tetraplegia. Reconstructive hand surgery is thus recommended to make urological management more independent for a selected group of people with tetraplegia.

Characterization of beta-adrenoceptor subtypes in the ferret urinary bladder in vitro and in vivo.

In the present study, the beta-adrenoceptor subtypes distributed in the detrusor of the ferret were investigated in functional experiments in vitro and in vivo using a variety of beta-adrenoceptor agonists and antagonists. All the beta-adrenoceptor agonists tested relaxed the isolated detrusor strip, the rank order of potency being (+/-)-(R*, R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]phenoxy]- acetic acid sodium (BRL 37344A)>(+/-)-4-(3-t-butylamino-2-hydroxypropoxy) benzimidazol-2-one (CGP-12177A), isoprenaline and (R, R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethylamino]propyl]-1, 3-benzodioxole-2,2-dicarboxylate (CL 316,243)>dobutamine and procaterol. In antagonist experiment, 3-(2-allylphenoxy)-1-[(1S)-1,2, 3,4-tetrahydro-naphth-1-ylamino]-(2S)-2-propanol hydrochloride (SR 58894A), but neither 2-hydroxy-5(2-((2-hydroxy-3-(4-((1-methyl-4-trifluoromethyl)1H-imidaz ole-2-yl)-phenoxy)propyl)amino)ethoxy)-benzamide monomethane sulphonate (CGP-20712A) nor erythro-(+/-)-1-(7-methylindan-4-yloxy)-3-isopropylaminob utan-2-ol hydrochloride (ICI-118,551), caused a rightward shift of the concentration-relaxation curve for isoprenaline. In in vivo experiments, isoprenaline and CL 316,243 each reduced bladder pressure in a dose-dependent manner. CL 316,243 was the only drug that did not produce any significant influences on blood pressure and heart rate at doses that reduced bladder pressure. The present functional study provides the first evidence that relaxation of the ferret detrusor by beta-adrenoceptor activation is mediated mainly via the beta(3)-adrenoceptor, as in the human detrusor.

Role of supraspinal tachykinins for micturition in conscious rats with and without bladder outlet obstruction.

In order to clarify the role of supraspinal tachykinins in volume-induced micturition and in bladder hyperactivity secondary to bladder outlet obstruction, conscious, normal, female Sprague-Dawley rats were investigated cystometrically before and after intracerebroventricular administration of RP 67,580, a selective antagonist of neurokinin (NK)-1 receptors and/or SR 48,968, a selective antagonist of NK-2 receptors. In normal rats, RP 67,580 or SR 48,968, at a dose of 2 nmol, caused no marked changes in cystometric parameters. Higher doses (up to 20 nmol) caused dose-dependent decreases in micturition pressure and increased bladder capacity, micturition volume and residual urine. A combination of the two drugs, each at a dose of 2 nmol, significantly decreased micturition pressure and increased bladder capacity. In rats with bladder outlet obstruction, the antagonists suppressed micturition dose-dependently, producing urinary retention in two out of eight rats already at a dose of 2 nmol. At a dose of 20 nmol, dribbling incontinence, due to urinary retention, was seen in five out of ten rats. A combination of the two drugs (2 nmol of each drug) caused urinary retention in three out of nine animals and significantly increased bladder capacity, micturition volume and residual volume. The results suggest that outflow obstruction in rats increases the effects of tachykinins in supraspinal structures involved in micturition, and that antagonism of supraspinal NK-receptors may depress the micturition reflex. Whether or not this implies that supraspinal NK-receptors can be targets for drugs aimed for inhibiting bladder hyperactivity in humans should be explored.

Continent ileal pouch using the serous-lined principle.

OBJECTIVES: The flap valve principle is not easily applicable to an ileal pouch since a submucosal tunnel is difficult to create. We attempted to construct an ileal pouch with an umbilical stoma applying the serous-lined principle for both ureteral implantation and construction of a continent valve. METHODS: In 9 patients, a continent pouch with an umbilical stoma was created entirely from an ileal segment. Adopting the serous-lined principle, a continent valve was created by appendix in 2 cases, tapered ileum in 3 cases, and reconfigured ileum in 4 cases. These were implanted into the anterior suture line of the pouch and embedded into the serous-lined tunnel formed by the pouch wall. RESULTS: Patients can catheterize the pouch easily with a 14-Fr catheter. Postoperatively, pouch capacity is over 400 ml with complete continence. CONCLUSION: This technique can provide a simple and effective continent ileal pouch facilitating umbilical anastomosis. As a continent valve, the reconfigured ileal segment seems most useful for application of the serous-lined principle.

Role of the beta(3)-adrenoceptor in urine storage in the rat: comparison between the selective beta(3)-adrenoceptor agonist, CL316, 243, and various smooth muscle relaxants.

The objective of this study was to compare the effects of a beta(3)-adrenoceptor (beta(3)-AR) agonist on bladder function and cardiovascular parameters in rats with those of several drugs that act on smooth muscle. CL316,243 (beta(3)-AR agonist), isoproterenol (nonselective beta-AR agonist), procaterol (beta(2)-AR agonist), verapamil (Ca(2+) antagonist), and papaverine (antispastic drug) each evoked a concentration-dependent relaxation of the detrusor in vitro. They also reduced bladder pressure in anesthetized rats, the beta-AR agonists apparently being more potent than the other drugs. Atropine (muscarinic antagonist) neither relaxed detrusor strips nor reduced bladder pressure. In anesthetized rats, CL316,243 and atropine each had only a slight influence on blood pressure and heart rate, but isoproterenol, procaterol, verapamil, and papaverine significantly affected cardiovascular function at the same dose range as that required to reduce bladder pressure. In cystometry experiments, CL316,243 (10 microg/kg i.v.), verapamil (1 mg/kg i.v.), and papaverine (1 mg/kg i.v.) all significantly prolonged micturition interval and increased bladder capacity, but did not change the residual urine volume after a micturition contraction. Procaterol (100 microg/kg i.v.) prolonged the micturition interval and increased both bladder capacity and residual urine volume (all significantly). Atropine (100 microg/kg i.v.) reduced micturition pressure and increased residual urine volume (both significantly). Because the human detrusor, like the rat detrusor, relaxes on beta(3)-AR stimulation, we conclude that this beta(3)-AR agonist may have potential in pollakiuria (frequent urination) as a therapeutic agent without cardiovascular side effects.

Optimization of orthotopic colonic bladder: implantation of tubularized mucosal flap from colonic segment into demucosalized urethra.

If the urethral mucosa of a female could be replaced by another mucosa, one could augment the indication for orthotopic reconstruction of the bladder. A mucosal replacement technique for the female urethra is reported. A colonic mucosal flap formed from a colonic bladder was used in a patient with bladder cancer for whom cystectomy was indicated. For 3 years after the surgery, the patient has maintained satisfactory voiding and urethral function. There has been no evidence of a recurrence. The orthotopic bladder with the mucosal replacement technique can be applied to female patients who have a bladder cancer with a high risk of urethral recurrence.

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.