Detrusor Response Research Articles

Influence of Nerve Transsections and Combined Bladder Filling on Intravesical Electrostimulation-Induced Bladder Contraction in the Rat

BackgroundThe exact mechanisms of action of intravesical electrical stimulation (IVES) are not yet fully understood. ObjectiveTo gain more insight into the underlying mechanism(s) of the direct detrusor response during IVES by transsecting the dorsal roots and the pelvic nerve consecutively at different levels and to determine whether the efficiency of IVES to induce contraction could be enhanced by simultaneous bladder filling and IVES and by changing the bladder-filling grade. Design, Setting, and ParticipantsEighteen Sprague-Dawley rats underwent IVES (square-wave pulses at 10Hz, 20-ms pulse duration). MeasurementsIn seven rats, IVES-induced bladder-pressure development was studied after the bladder nerves were consecutively sectioned bilaterally at four different levels: no lesion, L6 dorsal roots, L6 ventral roots, pelvic nerve, and major pelvic ganglion with surrounding nerves. Bladder-pressure development induced by IVES with simultaneous bladder filling, by bladder filling alone, and by IVES alone was recorded in seven other rats, and bladder-pressure development induced by IVES with different grades of bladder filling was recorded in four rats. Results and LimitationsContraction during IVES was significantly weaker after consecutive section of more nerves (all p<0.001), but a small contraction (19±17% of baseline) could be elicited even after total decentralization. In the neurologically intact rats, separate stimulation and bladder filling gave contraction strengths similar to those of simultaneous bladder filling and stimulation, but the latter gave contraction after a significantly shorter stimulation time (both p<0.015). ConclusionsIVES-induced contraction is, for the major part, a nerve-mediated process. However, a small bladder-pressure rise was induced by direct bladder-wall stimulation after all nerves were cut. Simultaneous electrical stimulation and bladder filling needed much shorter stimulation times than bladder filling alone or stimulation alone. If confirmed in humans, this could shorten IVES sessions substantially without altering the contractile results and could indicate that summation of afferent potentials from different triggers is possible.

TAMSULOSIN'S EFFECT ON SYSTEMIC BLOOD PRESSURE AND REFRACTORY NON-NEUROGENIC VOIDING DYSFUNCTION IN A PEDIATRIC POPULATION

You have accessJournal of Urology1 Apr 2008TAMSULOSIN'S EFFECT ON SYSTEMIC BLOOD PRESSURE AND REFRACTORY NON-NEUROGENIC VOIDING DYSFUNCTION IN A PEDIATRIC POPULATION Brian A Vanderbrink, Jordan Gitlin, Sylvia Toro, Emily T Cupelli, and Lane S Palmer Brian A VanderbrinkBrian A Vanderbrink More articles by this author , Jordan GitlinJordan Gitlin More articles by this author , Sylvia ToroSylvia Toro More articles by this author , Emily T CupelliEmily T Cupelli More articles by this author , and Lane S PalmerLane S Palmer More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(08)60868-XAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "TAMSULOSIN'S EFFECT ON SYSTEMIC BLOOD PRESSURE AND REFRACTORY NON-NEUROGENIC VOIDING DYSFUNCTION IN A PEDIATRIC POPULATION." The Journal of Urology, 179(4S), p. 298 © 2008 by American Urological AssociationFiguresReferencesRelatedDetails Volume 179Issue 4SApril 2008Page: 298 Advertisement Copyright & Permissions© 2008 by American Urological AssociationMetricsAuthor Information Brian A Vanderbrink More articles by this author Jordan Gitlin More articles by this author Sylvia Toro More articles by this author Emily T Cupelli More articles by this author Lane S Palmer More articles by this author Expand All Advertisement PDF DownloadLoading ...

Cold environmental stress induces detrusor overactivity via resiniferatoxin‐sensitive nerves in conscious rats

We determined if cold environmental stress induced detrusor overactivity in conscious rats. We then examined the role of resiniferatoxin (RTX)-sensitive nerves in this response. Three days prior to cystometric investigation, the urinary bladders of 12 female rats were cannulated. Six of the rats were treated with RTX 24 hr prior to cystometric investigation. The rats were exposed to three ambient temperature conditions: room temperature (RT, 27 degrees C) for 20 min, low temperature (LT, 4 degrees C) for 40 min, and RT again for 20 min. During each exposure, cystometric patterns of the rats were recorded. Additionally, neuronal structures of urinary bladders were visualized by immunohistochemistry. When the conscious rats were suddenly transferred from RT to LT, the cooled rats exhibited micturition patterns of detrusor overactivity. After 20 min at LT, the response slowly improved. After returning to RT, the overactive detrusor response disappeared, reverting to patterns similar to those before transfer to LT. When the RTX-treated rats were exposed with cold stress, they also exhibited detrusor overactivity. However, it was significantly mitigated compared to the non-RTX-treated normal rats. The normal rats had distinct neuronal structures labeled with S100 and calcitonin gene-related peptide antibodies in the urinary bladders, but the RTX-treated rats had few. Detrusor overactivity of the conscious rats was induced by cold environmental stress. A portion of the cold-stress detrusor overactivity might be mediated by RTX-sensitive neurological pathway. The cold-stress model would be useful to investigate lower urinary tract functions.

Comparative pharmacological analysis of Rho-kinase inhibitors and identification of molecular components of Ca 2+ sensitization in the rat lower urinary tract

We aimed to compare the expression and function of molecular components of the RhoA/Rho-kinase signaling pathway in the contractile responses of detrusor, trigonal and urethral smooth muscle, using selective Rho-kinase inhibitors. Contractility studies and molecular approaches were employed to demonstrate the expression patterns and functional activity of the RhoA/Rho-kinase signaling pathway in the lower urinary tract. Frequency–response curves (1–32 Hz) and concentration–response curves (CRC) to carbachol (CCh, 0.01–30 μM), phenylephrine (PE, 0.01–300 μM) and endothelin-1 (ET-1, 0.01–100 nM) were significantly attenuated ( p < 0.01) following incubation with the Rho-kinase inhibitors H-1152 (0.1–1 μM), Y-27632 (1–10 μM) or HA-1077 (10 μM). Addition of Rho-kinase inhibitors also markedly reduced ( p < 0.01) the contractions evoked by either KCl (80 mM) or α,β-methylene ATP (α,β-mATP, 10 μM). Among the Rho-kinase inhibitors tested, H-1152 was approximately 9–16 times more potent than Y-27632 or HA-1077. In addition, basal tone of detrusor and trigonal strips was reduced following addition of Y-27632 (10 μM), H-1152 (1 μM) and HA-1077 (10 μM). The expression of RhoA, RhoGDI, leukemia-associated RhoGEF (LARG) and p115RhoGEF was similar among the detrusor, trigone and urethra, whereas Rho-kinase α, Rho-kinase β and PDZ-RhoGEF protein levels were significantly lower in the urethra. Components of the RhoA/Rho-kinase signaling are expressed in detrusor, trigonal and urethral smooth muscle and dynamically regulate contraction and tone. Manipulation of RhoGEF expression may provide further understanding of mechanisms involving Ca 2+ sensitization in the lower urinary tract.

Null mutation in macrophage migration inhibitory factor prevents muscle cell loss and fibrosis in partial bladder outlet obstruction

Idiopathic detrusor underactivity (DU) and detrusor decompensation which develops following partial bladder outlet obstruction (pBOO) are both associated with smooth muscle degeneration and fibrosis. Macrophage migration inhibitory factor (MIF), an important mediator of bladder inflammation, has been shown to promote fibroblast survival and muscle death in other tissues. We evaluated the hypothesis that MIF has similar actions in the bladder by studying detrusor responses to pBOO or sham surgery in anesthetized female mice rendered null for the mif gene (MIF KO) and in wild-type (WT) controls, all killed 3 wk after surgery. WT mice revealed intense MIF immunoreactivity in urothelial cells which decreased, without change in overall mif mRNA levels. Stereologically sound quantitative morphometric measurements were performed in the middetrusor region of each bladder. MIF KO bladders were normal in appearance, yet were 30-40% heavier, with increased middetrusor collagen and muscle, compared with WT controls. In WT mice, pBOO increased the collagen-to-muscle ratio 1.9-fold and middetrusor collagen 1.8-fold, while nucleated muscle counts were 22% lower. In MIF KO mice, by contrast, pBOO had no significant effect on any of these parameters. In primary bladder muscle cultures, treatment with rMIF protein increased TUNEL staining, raising the proportion of early and late apoptotic cells on flow cytometry. Our studies implicate MIF in the sequence of events leading to detrusor muscle loss and fibrosis in obstruction. They raise the possibility that strategies designed to antagonize MIF synthesis, release, or biological activity could prevent or delay DU and urinary retention.

The emergence of new drugs for overactive bladder

Overactive bladder is a common and distressing problem. Standard therapy is directed towards modifying the detrusor motor sensitivity and response via anticholinergic medication. Currently available medications are reviewed and alternative targets for treatment are presented.

Depressed Contractile Responses to Neurokinin A in Idiopathic but not Neurogenic Overactive Human Detrusor Muscle

ObjectiveThe role of tachykinins such as neurokinin A in regulating bladder function is unclear, but NK2 receptors seem to mediate contraction in the human bladder and it has been suggested that these peptides may have a role in the pathophysiology of bladder dysfunction. The present study investigates neurokinin receptor-mediated contractility of detrusor muscle in the idiopathic overactive and neurogenic overactive bladder and investigates the neurokinin receptor subtypes involved. MethodsHuman bladder was obtained from patients undergoing cystectomy (normal) or clam cystoplasty (idiopathic overactive) and from patients with spinal injuries (neurogenic overactive). Strips of isolated detrusor muscle were mounted in physiological Krebs-bicarbonate solution and cumulative concentration-response curves to 1nM to 300μM neurokinin A (NKA) were obtained in the absence and presence of neurokinin receptor antagonists, either the NK2 receptor-selective antagonist SR 48968 or the NK3 receptor-selective antagonist SB 223412. ResultsNKA evoked concentration-dependent contraction of normal, idiopathic, and neurogenic overactive detrusor strips. In idiopathic overactive detrusor muscle, NKA-induced contraction was significantly reduced relative to normal detrusor (0.031±0.005mg/g, n=11 versus 0.193±0.039mg/g, n=7). Sensitivity to the peptide was also significantly (p<0.01) reduced in idiopathic overactive detrusor, with mean pEC50 values (concentration producing 50% maximal response) of 6.62±0.16 (n=11) compared to 7.47±0.19 (n=7) in normal detrusor. In contrast, NKA-induced responses of neurogenic overactive detrusor were similar to those in normal detrusor, with a mean maximum contraction of 0.199±0.036mg/g (n=10) and mean pEC50 value of 7.85±0.16 (n=10). NKA curves in all groups were shifted to the right by the NK2 receptor-selective antagonist SR 48968 with high affinity, pKB values being similar in normal, idiopathic, and neurogenic overactive detrusor (8.85+0.08, n=14; 8.97±0.13, n=12; 8.73±0.12, n=8, respectively). In contrast the NK3 receptor-selective antagonist SB 223412 had a minimal effect on NKA responses and affinity values were low (pKB 5.81±0.11, n=12 in normal; 5.75±0.08, n=12 in idiopathic overactive, and 5.77±0.13, n=11 in neurogenic overactive). ConclusionThese data indicate that NKA-induced responses are impaired in detrusor muscle from idiopathic overactive human bladder, but not in detrusor muscle from neurogenic overactive bladder. The NK2 receptor subtype appears to mediate NKA responses in the normal, idiopathic overactive, and neurogenic overactive detrusor. This is important evidence suggesting a difference between the bladder pathophysiology observed in idiopathic versus neurogenic overactive detrusor.

Altered muscarinic receptor subtype expression and functional responses in cyclophosphamide induced cystitis in rats

In the in vitro study, it was investigated whether the expression of muscarinic receptors and cholinergic responses were altered in the situation of experimental cystitis. Rats were treated with cyclophosphamide intraperitoneally and the bladders were excised 36–100 h later. Immunohistochemistry and immunoblotting showed all subtypes of the muscarinic receptor (M1–M5) to be present in the specimens from inflamed urinary bladders and controls. In the cyclophosphamide-treated rats, the expression of muscarinic M5 receptors was increased by more than 40 times ( p < 0.01; n = 8) both in the smooth muscle and the urothelium. Both the maximal contractile response to carbachol and to a high potassium concentration was approximately halved in cyclophosphamide-treated tissues, whereas the reduction was substantially greater in response to low carbachol concentrations (< EC 50). The administration of 4-DAMP inhibited the carbachol-induced contractile responses of inflamed strips less potently than of controls, whereas pirenzepine and methoctramine showed equipotency in the two groups. The nitric oxide synthase inhibitor l-NNA increased the contractile effect of carbachol in inflamed detrusor strips, while it had no effect in controls. Immunoblotting showed endothelial nitric oxide synthase (eNOS) to be up-regulated in cystitis, and immunohistochemistry revealed the change to occur in the urothelium and in the suburothelial layer. The alteration of cholinergic detrusor responses in cyclophosphamide-treated rats depends mainly on a general detriment of contractility but also on indirect effects possibly via nitric oxide synthesis. The most prominent histological alterations occurred in the urothelium in which muscarinic M5 receptors increased in particular. The study further underlines that the urothelium may play significant roles in the pathogenesis of urinary bladder disorders such as interstitial cystitis.

Comprehensive urodynamics evaluation of 146 men with incontinence after radical prostatectomy

Objectives To assess the filling, storage, and voiding urodynamic parameters in a large group of men with urinary incontinence after radical prostatectomy. Methods We reviewed the videourodynamics testing results for 146 consecutive men referred for urinary incontinence after radical prostatectomy. Results The mean patient age was 69.0 years (range 48 to 85), and the mean interval since radical prostatectomy was 4 years (range 4 months to 19 years). All but four tests were performed more than 12 months postoperatively. Stress urinary incontinence (SUI) was demonstrated in 139 men (95%), with a mean abdominal leak point pressure of 59 cm H 2O. A statistically significant correlation was found between the leak point pressure and static urethral pressure profilometry measurements ( r = 0.46, P <0.0001). The mean urethral pressure profilometry measurements in those with SUI were significantly lower than in those without (46.6 versus 69 cm H 2O, P = 0.001). A total of 34 patients had diminished compliance or detrusor instability, but this was the sole finding in only 3. A hypocontractile detrusor response was seen in 49 patients, and 35 of these augmented voiding by abdominal straining. Patients with previous radiotherapy (n = 24) were more likely to have bladder outlet obstruction; the other parameters were similar to those in patients without radiotherapy. Conclusions Incontinence after radical prostatectomy is caused by intrinsic sphincter deficiency in the vast majority of patients. Urethral pressure profilometry measurements correlated with the severity of SUI, as measured by abdominal leak point pressure. Bladder outlet obstruction may coexist with SUI in a significant portion of patients. During voiding, a hypocontractile detrusor response may be seen, but the clinical significance of this finding is unclear.

Poster 12: Comparative Effects of 1- and 5-Week Ovariectomy on Contractile Function of the Rabbit

OBJECTIVE: The urinary bladder can be considered a target organ for the actions of estrogen. Decreases in circulating estrogen postmenopause have been associated with urinary bladder dysfunctions, including incontinence and detrusor instability. Recent studies indicate that these changes can occur quite quickly when circulating estrogen decreases after ovariectomy. The current study was designed to compare the effects of ovariectomy at 1 and 5 weeks on contractile responses of the rabbit detrusor. METHODS: Female New Zealand white rabbits were ovariectomized and evaluated for the in vitro effects on contractile function (field stimulation [2, 8, and 32 Hz], carbachol [10 uM], ATP [1 mM], and KCl [120 mM]) at 1 and 5 weeks after ovariectomy (n=4–6 rabbits for each group). A control group of 4 rabbits was evaluated simultaneously. RESULTS: 1) Ovariectomy resulted in no significant change in bladder weight at either 1 or 5 weeks. 2) Both 1- and 5-week ovariectomy resulted in decreased maximal contractile responses to 8 and 32 Hz FS. No significant decreases were noted for the maximal responses to ATP, carbachol, or KCl. 3) Both 1- and 5-week ovariectomy resulted in significant decreases in the rate of tension generation for 32 Hz. 4) One-week ovariectomy resulted in a significant decrease in the rate of tension generation to ATP, whereas 5-week ovariectomy resulted in significant and substantial decreases in the rate of tension generation for ATP, carbachol, and KCl. CONCLUSIONS: These findings demonstrate that bladder contractile function is significantly affected by ovariectomy. In previous studies, we have demonstrated that the first sign of contractile dysfunction is a decrease in the rate of tension generation rather than decreases in the maximal contractile responses. These studies indicate that the longer the rabbit is ovariectomized, the greater the level of contractile dysfunctions. Decreased contractile function of the urethra especially may relate to the increased incidence of incontinence postmenopause.

Regional differences in responses of rabbit detrusor to electrical and adrenergic stimulation: influence of outlet obstruction

To examine regional responses of control and obstructed rabbit detrusor strips to electrical and adrenergic stimulation, and determine whether outlet obstruction causes regional variations in blood flow throughout the detrusor, as the detrusor smooth muscle of the bladder body has previously been considered homogeneous in its pharmacological properties. Fourteen male rabbits had the bladder outlet surgically obstructed for 2 weeks and were compared with 10 unoperated control rabbits. Blood flow was measured with the bladder empty and at capacity, using fluorescent microspheres. Paired dorsal and ventral strips were harvested from the midline equatorial detrusor and electrically and adrenergically stimulated. Obstructed rabbits had significantly higher bladder capacities and bladder weights than control rabbits. Dorsal strips from both control and obstructed rabbits contracted in response to noradrenaline, whereas ventral strips relaxed. The addition of prazosin, a nonselective alpha1-adrenergic-receptor blocker, completely blocked the contraction in dorsal strips, but had no effect on responses of ventral strips. There was also a regional difference in response to electrical stimulation, with ventral strips generating significantly more tension than dorsal strips in both control and obstructed rabbits. There were no regional differences in detrusor blood flow. Obstruction resulted in significantly lower responses to all forms of stimulation, and significantly less blood flow throughout the detrusor. There are regional differences in adrenergic receptor function and response to electrical-field stimulation throughout control and obstructed rabbit detrusor, a region that was previously thought to be functionally homogeneous. These differences must be recognized and acknowledged to obtain accurate and reproducible data from in vitro studies of the bladder.

Hypoxia inhibits human bladder smooth muscle cell proliferation: a potential mechanism of bladder dysfunction.

Recent animal studies have suggested that bladder outflow obstruction causes bladder wall hypoxia during both the filling and the voiding phases of the micturition cycle. We have previously demonstrated that mechanical deformation of human detrusor leads to smooth muscle (SM) cell hypertrophy and hyperplasia, which may then contribute to hypoxia in the dysfunctional bladder. We hypothesise that the detrusor's response to a hypoxic environment contributes to bladder dysfunction. The aim of this study was to evaluate the effect of hypoxia on detrusor cell survival and growth. Normal human detrusor muscle was obtained at radical cystectomy and primary cultures were established. Cells were then cultured in the presence of 1% oxygen in a hypoxic chamber for different times. Apoptosis was assessed by propidium iodide DNA staining and flow cytometry. Proliferation was assessed by radiolabelled thymidine incorporation. Cell supernatants were retained for growth factor estimation by enzyme linked immuno-sorbent assay (ELISA), and total cell and nuclear extracts were isolated for Western blotting. SM cells responded to the presence of hypoxia through significant upregulation of survival factors hypoxia inducible factor (HIF 1alpha) and vascular endothelial growth factor (VEGF) in a time-dependent manner. Hypoxia did not induce cell death, but significantly reduced the rate of proliferation over time, associated with an increase in the cell cycle inhibitor p27kip1. In an in vitro human detrusor cell culture model, cells demonstrate a resistance to hypoxia-induced apoptosis but proliferation is inhibited. We suggest that the anti-proliferative effects of hypoxia may limit the ability of detrusor cells to respond to, and compensate for, alterations in their environment contributing to bladder dysfunction.

Developmental aspects of bladder function

A review was conducted of the current knowledge of fetal and postnatal development of autonomic bladder function in animals. Studies of fetal and neonatal bladder development have been done in many animal species. Development of normal bladder function requires coordination of a number of different systems and processes, and continues after birth during the early neonatal period. In many neonatal animals, micturition occurs only after stimulation of a perineal-to-bladder reflex triggered when the mother licks the perineal region, and bladder distension fails to stimulate micturition. Voiding resulting from the normal bladder-to-bladder spinobulbospinal reflex activated by bladder distension develops only slowly over the first few weeks of life as synaptic connections in the sacral parasympathetic nucleus mature. The neurogenic response of bladder strips from young neonates is more sensitive to inhibition by atropine than that of strips from older animals, suggesting that there are developmental changes in the contribution of non-adrenergic, non-cholinergic transmitters to the response of the bladder smooth muscle to intramural nerve stimulation. Release of acetylcholine from cholinergic nerves and the mechanisms required to transform muscarinic receptor stimulation into efficient bladder contraction and emptying are fully developed at birth, but contractile and relaxant responses to many other agonists, such as adenosine triphosphate and noradrenaline, are developmentally regulated. Changes in calcium influx and storage may be responsible for many of these changes. Fetal detrusor is exquisitely sensitive to nitric oxide. Electrical stimulation of precontracted fetal bladder strips causes relaxation, an effect that is not seen in adult tissues, and is decreased by inhibitors of the actions of nitric oxide. Development of bladder function occurs before the onset of puberty and therefore is not normally dependent on sex hormones. However, neonatal treatment with or depletion of sex hormones can modulate bladder function. In particular, alpha-adrenergic receptor-mediated contractile responses of bladder detrusor are increased by prepubertal castration, an effect that may result from increases in the density of alpha-adrenergic receptors and/or changes in alpha-adrenergic receptor subtype expression.

An analysis of clinicopathologic factors in uterine smooth muscle tumors

We aimed to compare the expression and function of molecular components of the RhoA/Rho-kinase signaling pathway in the contractile responses of detrusor, trigonal and urethral smooth muscle, using selective Rho-kinase inhibitors. Contractility studies and molecular approaches were employed to demonstrate the expression patterns and functional activity of the RhoA/Rho-kinase signaling pathway in the lower urinary tract. Frequency–response curves (1–32 Hz) and concentration–response curves (CRC) to carbachol (CCh, 0.01–30 μM), phenylephrine (PE, 0.01–300 μM) and endothelin-1 (ET-1, 0.01–100 nM) were significantly attenuated (p < 0.01) following incubation with the Rho-kinase inhibitors H-1152 (0.1–1 μM), Y-27632 (1–10 μM) or HA-1077 (10 μM). Addition of Rho-kinase inhibitors also markedly reduced (p < 0.01) the contractions evoked by either KCl (80 mM) or α,β-methylene ATP (α,β-mATP, 10 μM). Among the Rho-kinase inhibitors tested, H-1152 was approximately 9–16 times more potent than Y-27632 or HA-1077. In addition, basal tone of detrusor and trigonal strips was reduced following addition of Y-27632 (10 μM), H-1152 (1 μM) and HA-1077 (10 μM). The expression of RhoA, RhoGDI, leukemia-associated RhoGEF (LARG) and p115RhoGEF was similar among the detrusor, trigone and urethra, whereas Rho-kinase α, Rho-kinase β and PDZ-RhoGEF protein levels were significantly lower in the urethra. Components of the RhoA/Rho-kinase signaling are expressed in detrusor, trigonal and urethral smooth muscle and dynamically regulate contraction and tone. Manipulation of RhoGEF expression may provide further understanding of mechanisms involving Ca2+ sensitization in the lower urinary tract.

Effectiveness Of Intravesical Resiniferatoxin For Anticholinergic Treatment Refractory Detrusor Overactivity Due To Nonspinal Cord Lesions

Evidence suggests that unmyelinated C fibers become predominant in the mediation of the detrusor reflex in patients with chronic spinal cord lesions and possibly in idiopathic detrusor hyperactivity. Intravesical vanilloid therapy might be effective in treating refractory detrusor overactivity due to nonspinal cord lesion. This study investigated the clinical effect of intravesical resiniferatoxin in treating detrusor overactivity of nonspinal cord lesions refractory to anticholinergics. A total of 41 patients received intravesical resiniferatoxin therapy with 10 ml of 100 nM resiniferatoxin in 10% ethanol solution for 40 minutes. The clinical effects on a decrease in incontinence episodes and urodynamic study were evaluated at baseline and after treatment. Clinical improvement was considered if patients became dry or had a decrease in incontinence episodes of 50%. Therapeutic results were analyzed by disease category and type of initial detrusor response. Of the 41 patients 10 had neurogenic lesions, 18 had previous transurethral prostatectomy and 13 had idiopathic detrusor overactivity. There were 20 women and 21 men with a mean age of 73.6 years (range 43 to 82) and a symptom duration of 3.6 +/- 4.5 years. After resiniferatoxin treatment 21 patients had clinical improvement (51.2%) including 5 with neurogenic (50%), 11 with previous transurethral prostatectomy (61.1%) and 5 with idiopathic detrusor overactivity (38.5%). An improvement was found in 11 patients with type I initial response (84.6%), 3 patients with type II response (23%) and 7 patients with type III response (46.7%). The 21 patients with improvement had a significant increase in cystometric capacity (208 +/- 80.7 vs 287.2 +/- 118.6 ml, p = 0.001) and a significant decrease in detrusor pressure (33.6 +/- 11.1 vs 27.4 +/- 11.8 cmH(2)O, p = 0.047), but no significant difference in maximal flow rate and residual urine volume. Intravesical resiniferatoxin was effective in treating refractory detrusor overactivity in 51.2% of patients with nonspinal cord lesions. Patients with detrusor overactivity due to previous bladder outlet obstruction benefited the most. Detrusor contractility decreased after resiniferatoxin treatment in the group with improvement but did not influence voiding efficiency. The initial detrusor response to resiniferatoxin treatment might predict the clinical outcome.

Desensitisation of purinergic receptors enhances neurogenic detrusor responses in the bladder dome of the pig

Desensitisation of purinergic receptors enhances neurogenic detrusor responses in the bladder dome of the pig

Murine in vitro whole bladder physiology.

The function of the bladder is twofold: 1) to store urine at low pressure, and 2) under control of the nervous system, to generate a contractile force coordinated with a lowered urethral resistance that allows for emptying.20 Clinically, this system is most commonly affected by bladder outlet obstruction, and the response of the detrusor is remarkable in its variability. Experimentally, most investigators agree that after outlet obstruction, there is an increase in bladder mass seen irrespective of the model used. Within most experimental models of partial obstruction (as with humans), there exists a degree of variability in terms of detrusor response. Some bladders enter a state of compensation and are able to sustain elevated voiding pressures and empty satisfactorily. Others enter a state of decompensation and lose their ability to empty effectively.15 The molecular mechanisms for such decompensations are under current investigation, and may involve alterations in cytosolic calcium handling,19,21 disruptions in mitochondrial function,4 and changes in the expression of contractile filaments.1 In the late stages, as the bladder slides into the decompensated state, major depositions of extracellular matrix are seen in a variety of species.3,9,11

Categorización de receptores α1-adrenérgicos en el detrusor de pacientes con hbp obstructiva. estudio inicial en modelo animal de experimentación

IntroductionThe action of α1-adrenergic receptor antagonists in ameliorating irritation and obstruction in patients with bladder outlet obstruction (due to Benign Prostatic Hyperplasia-BPH) has been demonstrated. Although it is well known that α1-a receptors are responsible for prostate smooth muscle relaxation, the mechanism by which irritative bladder symptoms are improved is unknown. Different α1 receptor subtypes may be involved. The objective of this study is to investigate the changes in the α- adrenergic receptor populations in the obstructed detrusor, and to determine which subtype is proportionally increased in this situation (bladder outlet obstruction). Material and methodsThis was an in vivo study in an experimental model: male NZ (New Zealand) rabbits. The bladder neck of one group of rabbits was obstructed surgically using the technique proposed by Levin et al1,2. Subsequent to bladder catherisation with a 8Fr catheter, the bladder neck was exposed by means of a low medial abdominal incision. The bladder neck was tied with a 2/0 silk thread below the ureteral orifices. The catheter was taken out at the end of the intervention. The rabbits were sacrificed after 4 weeks using intracardiac pentothal and cystectomy was performed. A control group that did not undergo bladder obstruction were also sacrificed at this time, for the comparative study. Part of the detrusor was used for a pathological study and the rest for a physio-pharmacological study in which the organ was placed in a bath of adrenoceptor agonists (phenylephrine and noradrenaline) and antagonists WB101, AH11101A and BMY7378 (antagonists of the α1a, b, d, respectively). ResultsThe findings of the pathological study show that the bladder wall was thicker in the rabbits that underwent bladder obstruction. The physio-pharmacological studies demonstrate that the detrusor response to the selective α-1 adrenergic agonist was greater in the rabbits that underwent bladder obstruction, however detrusor contractility was decreased (KPSS). With bladder obstruction the α1d receptors were increased. Discussion and conclusionsReceptor-binding studies (Malloy et al)3 aim to differentiate the α-adrenoreceptor populations. These studies identify and quantitate the different receptor subtypes in tissue without taking into account their activity. The isometric and physio-pharmacological tests evaluate active receptors, i.e. those that respond to agonist and antagonist stimuli. This enables detrusor activity to be evaluated accurately. The results obtained in this investigational study support the hypothesis that there is a high statistically significant increase in the α1 adrenergic receptors in the obstructed detrusor. Furthermore, in agreement with previous molecular studies4, during prostate obstruction α1d is the predominate sub-population in the bladder. These findings may have patho-physiological, clinical and pharmacological implications. If this hypothesis which has been demonstrated in an experimental model, is also demonstrated in studies in humans, pharmacological development should not only be focussed on selective α1a receptor antagonists (prostate) but also on those of α1d, for relieving symptoms in patients with bladder outlet obstruction (BPH and prostatism).

Prognostic value of urodynamic testing in myelodysplastic patients

We herein describe the clinical progress of 42 myelodysplastic patients studied urodynamically and followed for a mean of 7.1 years. Urodynamic evaluation included urethral pressure profilometry, simultaneous determination of urethral pressure, intravesical pressure and external anal or external urethral sphincter electromyography with fluoroscopic voiding cystourethrography. Assessment of urethral function showed 36 patients (86 per cent) with an open vesical outlet and nonfunctional proximal urethra. Cystometrography revealed that 7 of 42 patients (17 per cent) had reflex detrusor activity: 4 with coordinated micturition and 3 with detrusorsphincter dyssynergia. Thirty-five patients (83 per cent) had areflexic detrusor dysfunction: 5 with atonic detrusor response and 30 with a progressive increase in pressure with increasing volume. The intravesical pressure at the time of urethral leakage was 40 cm. water or less in 20 patients and at pressures greater than this value in 22 patients. No patient in the low pressure group had vesicoureteral reflux and only 2 showed ureteral dilatation on excretory urography. In contrast, of the patients in the higher pressure group 15 (68 per cent) showed vesicoureteral reflux and 18 (81 per cent) showed ureteral dilatation on excretory urography. Thus, a striking relationship between the urethral closure pressure and intravesical pressure at the time of urethral leakage and the clinical course in this group of myelodysplastic patients is demonstrated. Every patient with a normally closed vesical outlet was continent on intermittent catheterization and an anticholinergic agent, while only 60 per cent of patients with open bladder outlets similarly treated achieved good urinary control and none was dry. An artificial sphincter device would seem to be a reasonable method to achieve urinary control in the latter patients but the detrusor response to filling also must be considered. Detrusor hypertonia should be controlled or controllable before a sphincter augmenting device can be used safely. Treatment options for patients with high urethral closure pressures include intermittent catheterization and anticholinergic medications or a sphincter ablative procedure to decrease the outlet resistance combined with anticholinergic therapy and implantation of an artificial sphincter. However, only longer followup will determine if these therapeutic regimens will prevent upper urinary tract deterioration.

EFFECTS OF THE NUCLEAR FACTOR-κB INHIBITORS 2-HYDROXY-4-TRIFLUOROMETHYLBENZOIC ACID AND ASPIRIN ON MICTURITION IN RATS WITH NORMAL AND INFLAMED BLADDER

We examined the effects of intravenous administration of the 2 nuclear factor-kappaB inhibitors aspirin and 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) on bladder filling and voiding in anesthetized and conscious rats. Disappearance of isovolumic bladder contractions after intravenous administration of different doses of aspirin and HTB in anesthetized, transurethrally catheterized rats was evaluated. Cystometry was performed in conscious rats during bladder infusion with saline or diluted acetic acid as well as in those with cyclophosphamide induced cystitis. Changes in bladder capacity and voiding pressure were evaluated after intravenous administration of test compounds. Aspirin induced a dose dependent disappearance of isovolumic bladder contractions in anesthetized rats with an extrapolated dose of 2.1 mg./kg. inducing 10 minutes of bladder quiescence. HTB was practically inactive, inducing a dose independent block of 3 to 4 minutes after intravenous administration of 1 to 10 mg./kg. In conscious rats with a bladder infused with saline aspirin was poorly active on bladder capacity, inducing a 20% increase 60 minutes after intravenous administration of 30 and 100 mg./kg. In rats with a bladder infused with acetic acid aspirin was much more active when injected at the initiation of inflammation and after 1 hour of irritant infusion. In this latter situation aspirin increased bladder capacity up to 60% after intravenous administration of 30 and 100 mg./kg. Similar results were obtained in rats with cyclophosphamide induced cystitis in which the bladder was infused with saline. In these cystometrography models 30 mg./kg. HTB intravenously was completely inactive. The results show that HTB is devoid of significant effects on the micturition reflex in the absence or presence of bladder inflammation, suggesting that acute inhibition of nuclear factor-kappaB does not influence bladder urodynamics in rats. In contrast, aspirin, which is a cyclooxygenase and nuclear factor-kappaB inhibitor, was always effective, indicating the important role of cyclooxygenase enzymes.