The Evidence Paradox of the Effectiveness between the Paediatric and Adult Stone-Forming Population: A Narrative Review.

AIM/OBJECTIVE: To identify trends in the evidence base regarding the effectiveness of using α-blockers in children versus adults and compare outcomes. METHODS: A literature search up using the key words including urolithiasis/renal/ureteric stone in children/paediatric population, medical expulsive treatment (MET), α-blocker/alfuzosin/tamsulosin/doxazosin. Included were randomized or controlled clinical trials in paediatric stone formers (aged ≤18 years). Outcome measures for assessment included the overall stone expulsion rate, expulsion time, the number of pain episodes and adverse drug effects and/or reactions. Further comparison of efficacy levels using respective studies from the adult population was performed in order to identify trends, similarities and differences. RESULTS: A total of 8,259 articles were identified. Full text evaluation was possible for 28 articles. Although the picture is clearer in the paediatric group, the lack of reproducible results in adults certainly poses serious questions about data collection, analysis and interpretation in each individual study. The apparent paradox is due to the methodological differences between studies. CONCLUSION: The effectiveness of α-blockers and other medication as MET needs to be studied in multi-institutional, double-blind, placebo-controlled studies that would aim to prove superiority to placebo in contemporary clinical situations, with realistic end points and standardized outcome measure determination.

Spinal neuronal cannabinoid receptors mediate urodynamic effects of systemic fatty acid amide hydrolase (FAAH) inhibition in rats.

AIMS: To test if urodynamic effects from systemic Fatty Acid Amide Hydrolase (FAAH) inhibition involve sacral spinal cannabinoid type 1 (CB1) or type 2 (CB2) receptors. METHODS: Male rats with or without partial urethral obstruction were used for cystometry or immunohistochemistry. Urodynamic effects of intravenous (IV) 0.3 mg/kg Oleoyl Ethyl Amide (OEtA; FAAH inhibitor), and intrathecal (IT) 5 µg rimonabant (CB1 antagonist) or 5 µg SR144528 (CB2 antagonist) were studied in awake rats. RESULTS: After administration of rimonabant or SR144528, non-obstructed rats with normal bladder function developed bladder overactivity (BO), which was counteracted by OEtA. OEtA also counteracted BO in obstructed rats. SR144528 did not affect bladder function in obstructed rats but counteracted the urodynamic effects of OEtA. Surprisingly, rimonabant (and AM251, another CB1 antagonist) reduced BO in obstructed rats, whereafter OEtA produced no additional urodynamic effects. CB1 expression increased in the sacral spinal cord of obstructed rats whereas no changes were observed for CB2 or FAAH. CONCLUSIONS: Urodynamic effects of systemic FAAH inhibition involve activities at spinal neuronal CB1 and CB2 receptors in normal and obstructed rats. Endogenous spinal CB receptor ligands seem to regulate normal micturition and BO. Altered spinal CB receptor functions may be involved in the pathogenesis of obstruction-induced BO. Neurourol. Urodynam. 35:464-470, 2016. © 2015 Wiley Periodicals, Inc.

Morphological and functional response to injury to the external urethral sphincter - similarities and differences between male and female rats.

AIMS: The objective of this study was to evaluate the similarities and differences of the urethral morphological and functional changes following external urethral sphincter EUS injury in male and female rats. METHODS: 30 female and 30 male age-matched Wistar rats were used in the experiments. Half of them underwent electrocauterization of the surrounding tissues lateral to the urethra at the level of the (EUS) and the others, a sham operation. At 2, 6, and 16 weeks after surgeries they underwent anesthetized cystometry, measurement of leak point pressure (LPP) and their urethras were harvested for morphological analyses. RESULTS: There were no differences in cystometric parameters between sex-time-matched animals, ensuring normal bladder function in the manipulated animals. The mean LPP in male and female rats was lower compared with sham animals. Age-time-matched sham operated male rats exhibited a higher LPP compared with female rats. The reduction in LPP comparing electrocauterized and sham time-matched animals was more pronounced in male rats than in female rats. Electrocauterization produced urethral collagen deposition and nerve damage in both male and female animals. Muscle atrophy and disruption also occurred, being more evident in female rats. CONCLUSIONS: The urethras of male and female rats exhibited a similar morphological and functional response to electrocauterization. The time-course evaluation revealed that the male animal model is as reliable, reproducible and long-lasting as the female model. Intact males had a higher LPP than female rats and the nerve injury led to a more drastic impairment of this mechanism.

AdVance and AdVance XP slings for the treatment of post-prostatectomy incontinence.

PURPOSE: To examine the outcomes with the AdVance XP and AdVance slings in the management of post-prostatectomy incontinence (PPI). METHODS: Eighty patients were treated with the AdVance resp. AdVance XP at one tertiary reference centre. The initial patients were implanted with the AdVance male sling with no associated surgery. Following the introduction of the AdVance XP sling, subsequent patients were implanted with the AdVance XP slings. Measurements included: daily pad usage, 24-h pad weight test, International Quality of Life Questionnaire, International Consultation on Incontinence Questionnaire Short Form and the Patient Global Impression of Improvement. Adverse events were recorded. RESULTS: Follow-up was available for 39 and 41 patients treated with the AdVance and AdVance XP slings, respectively. At a median follow-up of 24.7 months, 69.3 % of patients could be classified as cured or improved in the AdVance group and at a median follow-up of 11.9 months, 90.3 % of AdVance XP-treated patients. At 3-month follow-up, 96.8 and 97.3 % of patients could be classed as cured or improved in the AdVance and AdVance XP groups, respectively (not significant). There were no perioperative complications. Two AdVance and three AdVance XP serious post-operative complications were reported, which were resolved following treatment. QOL was improved in both treatment groups. CONCLUSIONS: Both the AdVance and the AdVance XP slings are effective and safe for the treatment of PPI.

New concepts for the treatment of male lower urinary tract symptoms.

PURPOSE OF REVIEW: New insights into how lower urinary tract symptoms (LUTS) develop in the presence (or absence) of benign prostatic hyperplasia (BPH) led to a change of terminology from BPH to LUTS, and to the revelation that several other (not only prostatic) molecular structures are of value in treating LUTS. This review aims to summarize what new we know about 'why the prostate grows large', and what kind of therapeutic implications that bears, and second to present several new compounds, which show promising results in preclinical testings in regards to LUTS. RECENT FINDINGS: Apart from the old concept of mainly hormone-dependent prostate growth, new concepts on BPH cause include genetic reasons, correlations with metabolic disorders, as well as an inflammatory origin. New pharmacological compound classes, which might be of value in treating LUTS, are transient receptor potential V member 1 antagonists, fatty acid amide hydrolase inhibitors, soluble guanylyl cyclase stimulators and activators, Rho-kinase inhibitors, and purinergic receptor antagonists. SUMMARY: New concepts on BPH cause show interesting approaches, but are still in early stages. They carry, however, the highest prospect to bring up causal treatments. Some new compounds related to LUTS are on the verge to switch 'from bench to bedside'.

Inhibition of peripheral FAAH depresses activities of bladder mechanosensitive nerve fibers of the rat.

PURPOSE: FAAH degrades endocannabinoids and fatty acid amides. FAAH inhibition reduces micturition frequency and counteracts bladder overactivity in rats. We studied the effects of the peripherally active selective FAAH inhibitor URB937, and the CB1 and CB2 receptor antagonists rimonabant and SR144528, respectively, on single unit afferent activity of primary bladder afferents in rats. MATERIALS AND METHODS: Female Sprague Dawley® rats were anesthetized. Single unit afferent activity of Aδ or C-fibers from the L6 dorsal roots was recorded during bladder filling before and after URB937 administration with or without rimonabant or SR144528. Drugs (1 mg/kg) were given intravenously. FAAH, CB1 and CB2 expression, and expression of the sensory marker CGRP in the L6 dorsal root ganglion were compared by immunofluorescence. RESULTS: A total of 102 single afferent fibers (48 Aδ and 54 C-fibers) were isolated from 57 rats. URB937 decreased single unit afferent activity of C-fibers to a mean ± SEM of 78% ± 9% and of Aδ-fibers to a mean of 67% ± 7% while increasing bladder compliance to a mean of 116% ± 3%. The effects of URB937 on single unit afferent activity and bladder compliance were counteracted by rimonabant or SR144528. Rimonabant increased single unit afferent activity of each fiber type but SR144528 affected only Aδ-fiber activity. CGRP positive L6 dorsal root ganglion neurons showed strong FAAH, CB1 and CB2 staining. CONCLUSIONS: To our knowledge we report for the first time that inhibiting peripheral FAAH depresses the Aδ and C-fiber activity of primary bladder afferents via CB1 and CB2 receptors. CB antagonists alone exerted facilitatory effects on single unit afferent activity during bladder filling in rats. The endocannabinoid system may be involved in physiological control of micturition as regulators of afferent signals.

Bladder function in a cannabinoid receptor type 1 knockout mouse.

OBJECTIVE: To evaluate bladder function in an established cannabinoid type 1 (CB1) receptor knockout (KO) mouse model via organ-bath (in vitro) and urodynamic (cystometric; in vivo) experiments. MATERIALS AND METHODS: In all, 20 8-week-old female wildtype (WT) mice (C57BL/6) and 20 age-matched CB1 KO mice were used. Six mice from each group were used for the organ-bath experiments, where the contractile responses of bladder tissue strips after carbachol exposure (carbachol concentration response curve [CCRC]; myogenic contraction) and during electrical field stimulation (EFS; neurogenic contraction) were assessed. In all, 14 mice per group were used for cystometric experiments without any anaesthesia, in which standard urodynamic variables were assessed 3 days after bladder catheterisation. RESULTS: The CCRCs of bladder strips from CB1 KO mice were similar to those of WT mice. However, during EFS the bladder strips from the CB1 KO mice had significantly lower contractile responses than WT preparations, indicating that in CB1 KO mice the neuronal component of bladder contraction was different. In cystometric experiments the CB1 KO mice had a higher micturition frequency (shorter mean [sem] inter-micturition interval of 3.24 [0.29] vs 7.32 [0.5] min), a lower bladder capacity (0.09 [0.01] vs 0.18 [0.01] mL) and micturition volume (0.07 [0.01] vs 0.14 [0.01] mL), a lower bladder compliance (0.007 [0.001] vs 0.02 [0.002] mL/cmH2 O), and higher spontaneous bladder activity (5.1 [0.5] vs 2.6 [0.6] cmH2 O) than WT mice (all P < 0.05, Student's t-test). In WT mice, systemic administration of rimonabant (SR141716), a CB1 receptor antagonist, resulted in urodynamic changes similar to those seen in the CB1 KO mice. CONCLUSIONS: In vitro, bladder strips from CB1 KO mice responded to muscarinic receptor stimulation similarly as the WT controls, but were less responsive to electrical stimulation of nerves. In vivo, CB1 KO mice had a higher micturition frequency and more spontaneous activity than WT mice. The present findings suggest that CB1 receptors are involved in peripheral and central nervous control of micturition.

New strategies in treating male lower urinary tract symptoms.

PURPOSE OF REVIEW: Improved understanding of the pathogenesis of lower urinary tract symptoms (LUTS) has led to the development of new drugs to treat male LUTS. The review aims to give an overview to the new drugs and to compounds in the pipeline. RECENT FINDINGS: Tadalafil, a phosphodiesterase type 5 inhibitor, is a drug newly approved for the treatment of male LUTS and a true new challenger for the current standard treatment with alpha1 blockers, particularly in men with concomitant erectile dysfunction. Botulinum toxin and mirabegron, a beta3 agonist, might be of value in treating persistent storage LUTS. Intraprostatic injections with botulinum toxin, NX-1207, and PRX302, need further evaluation but might be treatment alternatives in the future. Similarly, vitamin D3 receptor analogues (e.g., elocalcitol), gonadotropin-releasing hormone antagonists (e.g., cetorelix), and modulators of the cannabinoid system (e.g., fatty acid amide hydrolase inhibitors) need further evaluation in clinical studies. Other compounds, such as transient receptor potential vanilloid antagonists, Rho kinase inhibitors, purinergic receptor blockers, and endothelin targeting drugs, are still at experimental stages. SUMMARY: Novel drugs for the treatment of male LUTS have been introduced recently. Clinical practice along with further trials will have to prove their value, along with other compounds that are still in their early phase of development.

Characterization of bladder function in a cannabinoid receptor type 2 knockout mouse in vivo and in vitro.

AIMS: The contribution of individual CB receptors (CB1 R and CB2 R) to normal micturition has not been clearly defined. Our goal was to study if differences in urodynamic parameters or in vitro bladder contractility can be demonstrated between CB2 R knockout (CB2 RKO) and C57BL/6J control (wild type, WT) mice. METHODS: Female WT and CB2 RKO mice underwent bladder catheterization and cystometry was performed after 2 and 3 days. Cystometric evaluations were performed in awake animals without drug administration, and WT were also given HU-308 (CB2 R agonist) followed by AM630 (CB2 R antagonist). Bladders were removed for in vitro assessment of contractile responses to carbachol and electrical field stimulation (EFS). RESULTS: CB2 RKO mice had significantly higher intercontraction intervals (ICIs), bladder capacity (BC) and compliance (Bcom) than WT controls (P < 0.05). In WT mice, BC and ICI were increased from baseline by HU-308 exposure, and then returned to baseline levels after AM630 administration (P < 0.05). There were no differences in contractility after carbachol or EFS between the groups. CONCLUSIONS: Lack of CB2 R was associated with longer ICI and higher BC and Bcom than its presence (WT controls). This was unexpected since in WT, an increase in BC and ICI from baseline was observed after CB2 R agonist administration, and this action was reversed by a CB2 R antagonist. Since there were no differences in the in vitro responses to carbachol and EFS in bladder strips, it may be speculated that the urodynamic differences are caused by a change in the central nervous micturition control in CB2 RKO animals. Neurourol. Urodynam. 33:566-570, 2014. © 2013 Wiley Periodicals, Inc.

Presence of phosphodiesterase type 5 in the spinal cord and its involvement in bladder outflow obstruction related bladder overactivity.

PURPOSE: Phosphodiesterase type 5 inhibitors were recently introduced as a new treatment option for men with lower urinary tract symptoms. Safety and clinical effectiveness are well documented but the mode of action is still unclear. We determined and compared the expression of phosphodiesterase type 5 in the spinal cord of normal (sham operated) rats and rats with partial urethral obstruction induced bladder overactivity. We also assessed the urodynamic effects of intravenously and intrathecally administered sildenafil in the rats to determine whether phosphodiesterase type 5 inhibitors exert effects on the sacral spinal cord. MATERIALS AND METHODS: A total of 65 male Sprague-Dawley rats were used for molecular/morphological and functional experiments. Bladder overactivity was induced via surgical partial urethral obstruction in 39 of 65 rats. Spinal phosphodiesterase type 5 expression was assessed by histology and polymerase chain reaction. The effects of sildenafil administered intravenously or intrathecally were studied urodynamically. RESULTS: Phosphodiesterase type 5 was expressed in various regions of the lumbosacral spinal cord, including the sacral regions of micturition control. Expression was similar in normal rats and rats with partial urethral obstruction/bladder overactivity. In normal rats intravenous and intrathecal sildenafil had no urodynamic effect. When administered intravenously and intrathecally to rats with partial urethral obstruction/bladder overactivity, sildenafil decreased micturition frequency and bladder pressure. Doses tested intrathecally had no effect when given intravenously. CONCLUSIONS: Phosphodiesterase type 5 is expressed in the rat spinal cord. Intravenous sildenafil may exert part of its urodynamic effect in rats with partial urethral obstruction/bladder overactivity via an effect on the sacral spinal cord.

Spinal cord FAAH in normal micturition control and bladder overactivity in awake rats.

PURPOSE: We assessed whether spinal inhibition of the cannabinoid degrading enzyme FAAH would have urodynamic effects in normal rats and rats with bladder overactivity induced by partial urethral obstruction or prostaglandin E2. We also determined the expression of FAAH, and the cannabinoid receptors CB1 and CB2 in the sacral spinal cord. MATERIALS AND METHODS: We used 44 rats for functional (cystometry) and Western blot experiments. The FAAH inhibitor oleoyl ethyl amide (3 to 300 nmol) was administered intrathecally (subarachnoidally) or intravenously. The expression of FAAH and CB1/CB2 receptors was determined by Western blot. RESULTS: Oleoyl ethyl amide given intrathecally affected micturition in normal rats and rats with bladder overactivity but effects were more pronounced in the latter. In normal rats oleoyl ethyl amide only decreased micturition frequency, while it decreased frequency and bladder pressures in rats with bladder overactivity. Intravenous oleoyl ethyl amide (3 to 300 nmol) had no urodynamic effect. FAAH and CB1/CB2 receptors were expressed in the rat sacral spinal cord. The expression of CB1/CB2 receptors but not FAAH was higher in obstructed than in normal rats. CONCLUSIONS: FAAH inhibition in the sacral spinal cord by oleoyl ethyl amide resulted in urodynamic effects in normal rats and rats with bladder overactivity. The spinal endocannabinoid system may be involved in normal micturition control and it appears altered when there is bladder overactivity.

Stem cell therapy ameliorates bladder dysfunction in an animal model of Parkinson disease.

PURPOSE: Different cell based therapies have been tested, focusing on motor function. We evaluated the effect of human amniotic fluid stem cells and bone marrow derived mesenchymal stem cells (ALLCELLS, Emeryville, California) on bladder dysfunction in a rat model of Parkinson disease. MATERIAL AND METHODS: A nigrostriatal lesion was induced by 6-hydroxydopamine in 96 athymic nude female rats divided into 3 treatment groups. After 2 weeks the groups were injected with human amniotic fluid stem cells, bone marrow derived mesenchymal stem cells and vehicle for sham treatment, respectively. At 3, 7, 14 and 28 days the bladder function of 8 rats per group was analyzed by conscious cystometry. Brains were extracted for immunostaining. RESULTS: The nigrostriatal lesion caused bladder dysfunction, which was consistent in sham treated animals throughout the study. Several cystometric parameters improved 14 days after human amniotic fluid stem cell or bone marrow derived mesenchymal stem cell injection, concomitant with the presence of human stem cells in the brain. At 14 days only a few cells were observed in a more caudal and lateral position. At 28 days the functional improvement subsided and human stem cells were no longer seen. Human stem cell injection improved the survival of dopaminergic neurons until 14 days. Human stem cells expressed superoxide dismutase-2 and seemed to modulate the expression of interleukin-6 and glial cell-derived neurotrophic factor by host cells. CONCLUSIONS: Cell therapy with human amniotic fluid stem cells and bone marrow derived mesenchymal stem cells temporarily ameliorated bladder dysfunction in a Parkinson disease model. In contrast to integration, cells may act on the injured environment via cell signaling.

Mid-term results for the retroluminar transobturator sling suspension for stress urinary incontinence after prostatectomy.

OBJECTIVE: • To evaluate prospectively the efficacy of the retroluminar transobturator male sling (AdVance® sling) for the functional treatment of stress urinary incontinence (SUI) after prostatectomy. PATIENTS AND METHODS: • A total of 137 patients with grade II-IV SUI, resulting from radical prostatectomy, were treated with the AdVance® sling in a prospective clinical study. In all, 11 patients were lost to follow-up. A total of 17 patients (13.5%) had additional adjuvant radiotherapy before sling implantation. • Before and after sling implantation, a standardized 1-h pad test was performed and post-void residual urine, uroflowmetry, quality-of-life scores and the International Index of Erectile Function (IIEF-5) were assessed. • When calculating the cure and improvement rates, 'cure' was defined as no pad use or one dry prophylactic pad; and 'improved' was defined as 1-2 pads or reduction of pads ≥ 50%. RESULTS: • After a median (range) follow-up of 27 (20-37) months, and a mean follow-up of 27.2 months, the success rate was 75.4% with 51.6%'cured' and 23.8%'improved'. • Overall daily pad use, urine loss in the 1-h pad test and quality-of-life scores improved significantly after sling implantation. • Compared with 1-year follow-up data, no worsening over time was noticed and no additional complications were seen. CONCLUSION: • With a mid-term follow-up, the retroluminar transobturator male sling is an effective, safe and attractive treatment option for SUI after radical prostatectomy. Results are stable over time.

Rodent models for urodynamic investigation.

Rodents, most commonly rats, mice, and guinea pigs are widely used to investigate urinary storage and voiding functions, both in normal animals and in models of disease. An often used methodology is cystometry. Micturitions in rodents and humans differ significantly and this must be considered when cystometry is used to interpret voiding in rodent models. Cystometry in humans requires active participation of the investigated patient (subject), and this can for obvious reasons not be achieved in the animals. Cystometric parameters in rodents are often poorly defined and do not correspond to those used in humans. This means that it is important that the terminology used for description of what is measured should be defined, and that the specific terminology used in human cystometry should be avoided. Available disease models in rodents have limited translational value, but despite many limitations, rodent cystometry may give important information on bladder physiology and pharmacology. The present review discusses the principles of urodynamics in rodents, techniques, and terminology, as well as some commonly used disease models, and their translational value.

Development of bladder dysfunction in a rat model of dopaminergic brain lesion.

AIMS: Parkinson's disease (PD) is one of the most common neurological disorders causing lower urinary tract dysfunction. We evaluated the temporal development of bladder dysfunction in rat PD model where urodynamic changes were induced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB). METHODS: Female Sprague-Dawley rats underwent a unilateral stereotaxic injection of 6-OHDA or vehicle (sham group) into the MFB. Cystometry was performed in conscious animals at 3, 14, and 28 days after the injury. Aged-matched unlesioned rats were used as healthy controls. RESULTS: Three days after lesion 6-OHDA rats showed higher threshold (TP), maximum pressures (MP), and spontaneous activity (SA) compared to healthy controls. Sham animals exhibited higher TP. After 14 days 6-OHDA rats had also higher micturition frequency, decreased bladder capacity, micturition volume and bladder compliance (Bcom) compared to sham and healthy controls. Sham animals showed lower Bcom and higher MP and SA. After 28 days, 6-OHDA rats exhibited the same changes as those in 14 days, while sham-operated animals showed parameters similar to those in healthy controls. CONCLUSIONS: These findings suggest that 6-OHDA lesion of the MFB causes bladder dysfunction already after 3 days. A pattern of detrusor overactivity was more clearly defined 14 days after the injection and persisted for 28 days. Cystometry may be a useful tool to study the pathophysiology of bladder dysfunction in PD, and urodynamic parameters may possibly be used to evaluate the effects of therapeutic interventions.

Beta3-adrenoceptors in the rat sacral spinal cord and their functional relevance in micturition under normal conditions and in a model of partial urethral obstruction.

AIMS: Beta3-adrenoceptor selective agonists are evaluated as a new treatment for patients with lower urinary tract symptoms . It is believed that ß3-AR selective agonists exert their effects via a peripheral site of action. However, ß3-ARs have been found in brain tissue. This study examined whether ß3-ARs are present in rat sacral spinal cord, and whether there are differences in ß3-AR expression between normal and partial urethral obstruction (PUO) animals, and furthermore assessed the functional relevance of spinal ß3-ARs for micturition. METHODS: Thirty-eight male Sprague-Dawley rats underwent either PUO or sham-operation. Two weeks after operation, half of the animals were used for histomorphological analysis. Remaining animals were used for functional experiments, where a ß3-AR selective agonist, BRL 37344, was given intrathecally. Bladder function was assessed by continuous cystometry in non-anesthetized animals before and after drug administration. RESULTS: Beta3-ARs were found in sacral spinal cord segments with an accumulation in the ventral horn. There was a significant increase of ß3-AR expression in obstructed rats. In functional experiments obstructed rats showed increased bladder weight, micturition frequency, spontaneous activity, and bladder pressures (all P < 0.05) compared to controls. Intrathecally administered BRL 37344 showed no effect in non-obstructed rats. In obstructed rats intrathecal BRL 37344 significantly reduced bladder pressures, spontaneous activity, and micturition frequency (all P < 0.05). CONCLUSIONS: Beta3-ARs are present in rat sacral spinal cord, and are significantly up-regulated after PUO. Besides their well-established peripheral site of action in the treatment of voiding dysfunction, ß3-AR selective agonists might exert relevant effects at a central nervous site of action.

Vascular therapy for radiation cystitis.

PURPOSE: The underlying pathology of radiation cystitis is cellular and vascular damage followed by increased fibrosis and inflammation. This study was to determine if neovascular-promoting therapy could reduce the pathological changes in the bladder wall associated with pelvic irradiation. METHODS: Adult female Lewis inbred rats were irradiated with a single dose of 20 Gy directed at their bladder. Four weeks later, 30 rats were divided equally into one of three treatment groups for bladder wall injection of: (1) PBS (Control); (2) PBS containing 50 ng vascular endothelial growth factor (VEGF (165)); or (3) PBS containing 1 × 10(6) rat endothelial cells (EC). Age-matched non-irradiated rats (n = 10) served as untreated controls. At either 1.5 or 3 months following radiation, bladders were analyzed for collagen deposition using Masson's Trichrome staining of collagen and muscle and vascularization using Von Willebrand factor staining of ECs. Quantitative-PCR was used to examine markers of angiogenesis, hypoxia, and fibrosis. RESULTS: The collagen/muscle ratio was doubled in the control group 3 months post-irradiation (P < 0.05 vs. non-irradiated bladders). Both ECs and VEGF inhibited increases in collagen content (P < 0.05 vs. control). Similarly, irradiation reduced bladder wall vessel counts compared to non-irradiated controls (P < 0.05) and both ECs and VEGF maintained vessel counts similar to that of non-irradiated controls (P < 0.05). PCR analysis showed a higher expression of neovascular markers (CD31, KDR) in the EC and VEGF groups compared to non-irradiated controls (P < 0.05). CONCLUSIONS: Angiogenesis therapy may be useful in the prevention and/or treatment of the underlying pathology of radiation cystitis.

Spinal effects of the fesoterodine metabolite 5-hydroxymethyl tolterodine and/or doxazosin in rats with or without partial urethral obstruction.

PURPOSE: The combination of muscarinic receptor and alpha(1)-adrenoceptor antagonists is increasingly used for benign prostatic hyperplasia related lower urinary tract symptoms. In addition to the well established peripheral site of action, little is known about the central effects of muscarinic receptor antagonists and muscarinic receptor/alpha(1)-adrenoceptor antagonist combinations on bladder function, partly due to poor brain penetration after systemic administration. We assessed the effects of intrathecal 5-hydroxymethyl tolterodine, an active metabolite of fesoterodine, in obstructed and nonobstructed rats, and of combined intrathecal 5-hydroxymethyl tolterodine/doxazosin in a rat model of partial urethral obstruction. MATERIALS AND METHODS: We used 80 male Sprague-Dawley rats to test various doses of intrathecal 5-hydroxymethyl tolterodine and/or intrathecal doxazosin on urodynamic parameters. Urodynamic evaluation without anesthesia was done 3 days after bladder and intrathecal catheterization. Two weeks before urodynamics 40 rats underwent partial urethral obstruction. RESULTS: Intrathecal 5-hydroxymethyl tolterodine had no urodynamic effects in nonobstructed rats. Compared to controls obstructed rats had increased bladder pressure and weight, and voiding frequency. In obstructed rats 5-hydroxymethyl tolterodine restored urodynamic parameters to those seen in nonobstructed animals. Doxazosin had effects similar to those of intrathecal 5-hydroxymethyl tolterodine. When the 2 drugs were combined, at the doses used only small additional effects were observed. CONCLUSIONS: Urodynamic changes in obstructed rats can be normalized by intrathecal 5-hydroxymethyl tolterodine and by intrathecal doxazosin. The central pathways on which the 2 drugs act seem to be up-regulated with partial urethral obstruction and less relevant under normal conditions.

Bladder dysfunction in a new mutant mouse model with increased superoxide--lack of nitric oxide?

PURPOSE: Nitric oxide mediates urethral smooth muscle relaxation and may also be involved in detrusor activity control. Mice with mutation in the Immp2l gene have high superoxide ion levels and a consequent decrease in the bioavailable amount of nitric oxide. We studied bladder function in this mouse model. MATERIAL AND METHODS: Young male mutants at ages 4 to 6 months, old female mutants at age 18 months and healthy WT age matched controls were used. The detrusor contractile response to carbachol and electrical field stimulation was tested in isolated detrusor strips in organ baths. In vivo bladder function was evaluated by cystometry in conscious animals. RESULTS: Young male mutants had significantly lower micturition and higher post-void residual volume than WT controls. They had pronounced voiding difficulty and strained when initiating micturition. Detrusor contractile responses to carbachol and electrical field stimulation were similar in mutant and WT mice. Old female mutant mice had lower bladder capacity and micturition volume, and higher micturition frequency and bladder-to-body weight ratio than WT controls. In the in vitro study detrusor strips from mutants showed a lower maximum response to carbachol. CONCLUSIONS: Mice with mutation in the Immp2l gene have bladder dysfunction, mainly characterized by emptying abnormalities in young males and increased detrusor activity in old females. Detrusor function was preserved in young males and impaired in old females. These animals are a natural model of oxidative stress with low bioavailable nitric oxide. Thus, they are interesting tools in which to evaluate the role of these conditions on bladder dysfunction.

Urodynamic evaluation of fesoterodine metabolite, doxazosin and their combination in a rat model of partial urethral obstruction.

OBJECTIVE: To evaluate the urodynamic effects of fesoterodine, a new antimuscarinic agent, alone and combined with doxazosin, in a rat model of partial urethral obstruction (PUO), as 35-83% of men with bladder outlet obstruction (BOO) secondary to benign prostatic hyperplasia (BPH) have overactive bladder (OAB) syndrome, and as the combination of alpha(1)-adrenoceptor- and muscarinic-receptor antagonists has been proposed to be beneficial for these patients. MATERIALS AND METHODS: Thirty-seven male Sprague-Dawley rats (250 g) had surgically induced PUO; 2 weeks later they were evaluated by cystometry with no anaesthesia or any restraint. After a 1-h period either 5-hydroxymethyl tolterodine (5-HMT, the active metabolite of fesoterodine, previously known as SPM 7605), doxazosin or a combination of both, was given intravenously (0.1 mg/kg body weight), and cystometry was continued for another 45 min. Fifteen healthy, age-matched rats served as a control. RESULTS: At 2 weeks after surgery the obstructed rats had an greater bladder weight, threshold pressure (TP) and micturition frequency (MF), and lower bladder capacity (BCap) and micturition volume (MV) than the controls. 5-HMT did not cause urinary retention in obstructed rats, but decreased TP, maximum pressure (MP), spontaneous bladder activity (SA) and, paradoxically, increased MF. Doxazosin alone decreased TP, MP, MF and increased BCap and MV. 5-HMT and doxazosin together did not depress the ability to empty the bladder, and showed decreased TP, MP and SA. CONCLUSIONS: 5-HMT, alone and in combination, did not impair the voiding ability in obstructed rats. Doxazosin counteracted some of the 'negative' effects of 5-HMT in this model (increase of MF) and did not attenuate the 'positive' effects (decrease of bladder SA). In this model, the combination of 5-HMT and doxazosin appeared to be urodynamically safe and well tolerated.