Up-regulation of endothelin-B (ETB) receptors and ETB receptor-mediated rabbit detrusor contraction in partial bladder outlet obstruction.

OBJECTIVE: To investigate, in a rabbit model of bladder outlet obstruction (BOO), whether ETB receptors initiate any contractile activity, and to assess the density of these receptors. MATERIALS AND METHODS: Partial BOO was produced in male New Zealand White rabbits, with age-matched sham-operated rabbits acting as controls. One and 3 weeks later, the detrusor and bladder neck strips were incubated in organ baths with either BQ788 (an ETB antagonist), BQ123 (an ETA antagonist) or vehicle. Concentration-response curves were constructed using IRL-1620 (a selective ETB agonist). Low-resolution autoradiography was performed on serial detrusor and bladder neck sections from control and partial BOO (3-week) rabbits using radioligands for ETA and ETB. RESULTS: In strips from controls and after 1 week of partial BOO, IRL-1620 induced no contractions, but after 3 weeks of BOO, IRL-1620 induced significant concentration-dependent detrusor contractions (producing 12%, 25% and 70% of the KCl response at 10-8, 10-7 and 10-6 mol/L, respectively). The ETA antagonist had no effect on IRL-1620-mediated contractions. In contrast, the ETB antagonist completely abolished these contractions. Autoradiography showed the presence of ETA and ETB receptors in the detrusor and bladder neck of normal and obstructed animals, and a significant up-regulation of ETA and ETB receptors only in the obstructed detrusor smooth muscle. CONCLUSIONS: In BOO, ETB receptors initiate detrusor contractile activity. This is a time-dependent process that may depend on the up-regulation of ETB receptors in the detrusor. Therefore, ETB receptors may play a role in the pathophysiology of partial BOO.     

Time-dependent up-regulation of neuronal 5-hydroxytryptamine binding sites in the detrusor of a rabbit model of partial bladder outlet obstruction

Serotonin (5-hydroxytryptamine; 5-HT), a vasoactive bioamine with potent contractile activity, is thought to act indirectly in the urinary bladder by the stimulation of its presynaptic receptors. This results in the release of acetylcholine (ACh), which then acts on muscarinic receptors to produce bladder contractility. Bladder outlet obstruction (BOO) can lead to detrusor instability associated with denervation supersensitivity to ACh. Using a rabbit model of partial BOO, we investigated whether there were any associated changes in the neuronal 5-HT binding sites. Partial BOO was induced in adult male New Zealand White rabbits. Sham-operated age-matched rabbits acted as controls. After 1, 3 and 6 weeks the urinary bladders were excised. Detrusor sections were incubated with [³H]-5-HT. Autoradiographs were generated and analysed densitometrically. The presence of nerves was detected using immunohistochemistry with NF200. Autoradiography demonstrated a time-dependent, significant (P < 0.0001) up-regulation of [³H]-5-HT binding sites in the detrusor smooth muscle after the induction of BOO. Immunohistochemistry confirmed that the [³H]-5-HT binding sites were neuronal. In the rabbit model of partial BOO there was a significant time-dependent up-regulation of neuronal [³H]-5-HT binding sites in the detrusor. This change may influence 5-HT-mediated ACh release, resulting in increased bladder contractility. This, in turn, may play a role in detrusor instability associated with denervation post-junctional supersensitivity. These results provide a possible rationale for further investigation into the use of 5-HT antagonists in the treatment of detrusor instability associated with BOO.     

Age-related changes in contractile force of rabbit detrusor muscle to prostaglandin E1, E2 and F2 alpha

Contractile responses of urinary bladder muscle strips to prostaglandin (PG) E1, E2 and F2 alpha were compared in young and old rabbits. All PGs tested caused an increase in contractile force of urinary bladder muscle strips from young (3 weeks) and old (greater than 2 years) rabbits. The contractile response was most marked with PGE2 at concentrations of 10(-10)-10(-7) M in muscle strips from both young and old rabbits. At a high concentration (10(-5) M), the contractile response was most marked with PGF2 alpha in young rabbit bladder muscle strips, whereas in old rabbit bladder muscle strips the magnitude of the responses to PGE2 and PGF2 alpha were equal at 10(-6) M and both were greater than the response to PGE1. The contractile response to PGE1 was greater in old detrusor than in young detrusor at concentrations greater than or equal to 10(-6) M, whereas the contractile response to PGE2 (10(-7)-10(-5) M) and PGF2 alpha (10(-6)-10(-5) M) were greater in young detrusor than in old detrusor. These data show that rabbit detrusor muscle shows a contractile response to PGE1, E2 and F2 alpha and that the magnitude of these responses vary with age.     

Nerve induced responses and force-velocity relations of regenerated detrusor muscle after subtotal cystectomy in the rat

AIMS: To study the pharmacological and mechanical properties of newly developed detrusor muscle after subtotal cystectomy, to explore if the regenerated detrusor has characteristics similar to the normal bladder base, from which it regenerated, or to the normal bladder body which it replaces. METHODS: Partial cystectomy was performed in female rats. Fifteen weeks later, detrusor strips were cut from supratrigonal and equatorial segments. Unoperated rats served as controls. Responses to field stimulation were obtained in the absence and presence of scopolamine, prazosin, and P2X1 blockade. Dose-response curves were obtained for carbachol, alpha,beta-methylene-ATP, and phenylephrine. Force-velocity data were obtained on maximally activated chemically skinned preparations. RESULTS: Maximal contractile response to field stimulation was 60% of that to high-K+ with no difference between strips from control and cystectomy bladders. Prazosin had no effect. Scopolamine decreased maximal response of supratrigonal strips to 62 +/- 6 (controls) and 61 +/- 4% (operated) of that without blocker. For equatorial strips the decrease was to 81 +/- 5 (controls) and 58 +/- 8% (operated). Frequency-response relations were obtained during blockade with scopolamine, alpha,beta-methylene-ATP, and prazosin. Supratrigonal strips showed a pronounced additional inhibition up to 40 Hz. Equatorial strips from controls were completely inhibited at all frequencies. Equatorial strips from operated bladders were inhibited up to 20 Hz but not at 40 and 60 Hz. Carbachol EC(50) values were similar in all groups. Maximum response to phenylephrine was 10-20% of high-K+ response. Maximal shortening velocity (Vmax) was similar in control supratrigonal and equatorial strips, but was significantly lower in the operated bladders. CONCLUSIONS: (1): A regional difference exists in pharmacological properties of control detrusor, with a considerable contractile response to stimulation remaining in the supratrigonal muscle after simultaneous cholinergic, adrenergic, and purinergic blockade. (2): The new detrusor was functionally well innervated with no supersensitivity to muscarinic stimulation. (3): The newly formed bladder body had pharmacological properties specific for the supratrigonal segment from which it had developed. (4): There was no regional difference in force-velocity characteristics of the control detrusor. (5): The lowered Vmax in the newly formed bladder might thus be related to growth and regeneration of muscle cells.     

膀胱出口梗阻后逼尿肌肾上腺素β3受体mRNA表达和作用

目的：初步研究前列腺增生患者膀胱出口梗阻后逼尿肌肾上腺素能β3受体亚型mRNA表达和作用.方法：选择前列腺增生膀胱出口无梗阻（对照组）9名和膀胱出口梗阻患者（实验组）21名,根据尿动力学将实验组分为逼尿肌稳定组和不稳定组,半定量RT-PCR方法检测三组逼尿肌β3受体亚型mRNA的表达,离体逼尿肌拉力实验检测β3受体激动剂对三组逼尿肌收缩力的影响.结果：对照组、逼尿肌稳定组和不稳定组β3受体mRNA相对含晕为（18.48±2.84）、（17.28±2.57）和（10.42±1.22）,不稳定组β3受体明显降低（P＜0.05）;β受体激动剂和β3受体激动剂诱导逼尿肌松驰效应呈浓度依赖性,对不稳定组作用小于稳定组和对照组（P＜0.05）,对照组与稳定组没有差别.结论：膀胱出口梗阻逼尿肌不稳定患者β3受体mRNA含量下降,并且对β3激动剂的松驰反应降低,逼尿肌肾上腺素能受体β3亚型可能参与膀胱出口梗阻后逼尿肌收缩力变化.     

Urothelial dysfunction and sensory protein expressions in patients with urological or systemic diseases and hypersensitive bladder

ObjectiveTo investigate the underlying pathophysiology in the urothelium of different lower urinary tract diseases (LUTDs) and in patients with overactive bladder (OAB) or hypersensitive bladder (HSB), including chronic inflammation, barrier proteins, and sensory functional receptors.Materials and MethodsA total of 156 patients, including 14 with idiopathic OAB, 11 with detrusor overactivity and inadequate contractility (DHIC), 19 with end-stage renal disease (ESRD) and HSB, 26 with spinal cord injury (SCI) and detrusor overactivity (DO), 23 with bladder outlet obstruction (BOO) and DO, 19 with diabetes mellitus (DM) and OAB, 20 with interstitial cystitis (IC), and 24 with ketamine cystitis (KC) were investigated for urothelial dysfunction and sensory protein expressions. Twenty control patients without LUTD were invited and separated into two groups for comparative studies. All participants had urodynamically proven DO or increased bladder sensation on video urodynamic studies. Urothelial dysfunction and functional receptor expressions were investigated and compared between patients with LUTD and controls.ResultsAll patient subgroups had significant increases in mast cell activation and apoptotic cell counts and a decrease in E-cadherin expression. P2X3 expression was significantly decreased in DHIC but was increased in BOO/DO. Urothelial M3 expression was significantly increased in patients with OAB, BOO/DO, DM/OAB, and KC. M2 expression was significantly decreased in DHIC but increased in patients with BOO/DO. β3-AR expression was significantly decreased in patients with OAB and increased in patients with DHIC, ESRD/HSB, DM/OAB, and KC. Patients with OAB and BOO/DO had significantly increased M2/β3-AR. Lower M2/β3-AR was associated with lower voiding efficiency and large postvoid residual (PVR) in DHIC, ESRD/HSB, and SCI/neurogenic detrusor overactivity (NDO).ConclusionPatients with OAB or HSB showed increased urothelial inflammation and lower barrier protein expression. Increased M3/β3-AR or M2/β3-AR in the urothelium was associated with OAB, whereas decreased M3/β3-AR or M2/β3-AR was associated with poor voiding efficiency and large PVR in LUTD.     

Up-regulation of endothelin (ETA and ETB) receptors and down-regulation of nitric oxide synthase in the detrusor of a rabbit model of partial bladder outlet obstruction

Bladder outlet obstruction (BOO) is associated with altered bladder structure and function. Endothelin-1 (ET-1) has mitogenic and potent contractile properties. There are two ET receptors: ET_A and ET_B. Nitric oxide synthase (NOS) is the enzyme responsible for the synthesis of nitric oxide (NO) which is involved in smooth muscle relaxation. We investigated whether there are any changes in the density of ET-receptors and NOS in the detrusor and bladder neck in a rabbit model of BOO. Partial BOO was induced in adult male New Zealand White rabbits. Sham operated age-matched rabbits acted as controls. After six weeks the urinary bladders were excised and detrusor and bladder neck sections incubated with radioligands for ET-1, ET_A and ET_B receptors and with [³H]–l-NOARG (a ligand for NOS). NADPH histochemistry was also performed. BOO bladder weights were significantly increased (P=0.002). ET-1 binding and ET_A receptor binding sites were significantly increased in the BOO detrusor smooth muscle (P=0.04, P=0.03 respectively) and urothelium (P=0.002, P=0.02 respectively). ET_B receptor binding sites were also significantly increased in the BOO detrusor smooth muscle (P=0.04). However, there was no change in the BOO bladder neck. NOS was significantly decreased in the detrusor smooth muscle (P=0.003) and urothelium (P=0.0002). In the bladder neck NOS was also significantly reduced in the urothelium (P=0.003). NADPH staining was decreased in the detrusor and bladder neck. The up-regulation of ET receptors along with the down-regulation of NOS in the detrusor may contribute to the symptoms associated with BOO. Since ET-1 has a mitogenic role, especially via its ET_A receptors, the increase in ET_A receptors may also be involved in detrusor hyperplasia and hypertrophy in BOO. ET antagonists may therefore have a role in the treatment of patients with BOO. Received: 24 March 1999 / Accepted: 25 June 1999     

A prospective evaluation of detrusor ultrastructural changes in bladder outlet obstruction

OBJECTIVES: To characterize the ultrastructure of detrusor smooth muscle from the bladders of symptomatic men with bladder outlet obstruction (BOO) caused by benign prostatic enlargement (BPE) and compare this with a matched control group; to determine how detrusor morphology relates to urodynamic findings and to develop a better understanding of the natural development of bladder dysfunction related to BOO. PATIENTS AND METHODS: Twelve men (mean age 66 years, range 52-77) with urodynamically confirmed BOO caused by BPE and 12 age-matched asymptomatic normally voiding controls (mean age 67.8 years, undergoing cystoscopy for other conditions) had detrusor biopsies taken endoscopically. The biopsies were processed for electron microscopy using standard methods. The specimens were randomized and examined at medium power (x 4000) by an examiner unaware of the urodynamic findings. Any ultrastructural patterns identified subjectively were noted. RESULTS: In the BOO group eight of the 12 men had a myohypertrophic pattern, half of which were associated with a degenerative pattern of hypocontractility. Of the remaining four patients, two had the degenerative pattern alone and two were normal. The six men whose biopsies had a degenerative pattern had consistent postvoid residual volumes of > 150 mL; the remainder all had volumes of < 150 mL. There were no ultrastructural abnormalities in the control patients. CONCLUSIONS: There are interesting qualitative ultrastructural changes in the obstructed detrusor, but they are not consistent enough to provide a reliable diagnostic tool. However, there may be an important relationship between the degenerative pattern and postvoid residual volume in BOO.     

Alterations in purinergic and cholinergic components of contractile responses of isolated detrusor contraction in a rat model of partial bladder outlet obstruction

OBJECTIVE: To study the effect of 3 weeks of partial bladder outlet obstruction (BOO), compared to a sham operation, on the cholinergic and purinergic components of detrusor contractile responses to agonists and to electrical field stimulation (EFS); the expression of P2X receptor subtypes was also examined. MATERIALS AND METHODS: Partial BOO was induced in female Sprague-Dawley rats by surgically applying a jeweller's silver 'jump' ring around the urethra, such that the urethra was constricted but not closed. Sham-operated female rats underwent an identical procedure without placement of a ring. RESULTS: After 3 weeks of partial BOO the rat bladders became significantly hypertrophied, doubling in weight. Spontaneous activity was markedly increased, but the contractile response to a single bolus of KCl (120 mM) was unaltered. The neurogenic-induced contractile responses of strips of detrusor from obstructed bladders were significantly greater than those from sham-operated bladders, and the responses of strips of detrusor from obstructed bladders to EFS showed a significantly greater atropine-sensitive component than sham-operated detrusor. However, the response of detrusor strips to EFS that was susceptible to desensitization by alpha,beta-methylene ATP was not significantly changed in obstructed bladders. The sensitivity of the strips from obstructed bladders to carbachol, ATP and beta,gamma-methylene ATP was less than in sham-operated detrusor. Immunohistochemical studies showed no difference in the P2X receptor subtypes expressed on detrusor smooth muscle from obstructed and sham-operated rats. CONCLUSION: In the rat, after moderate bladder hypertrophy, the atropine-sensitive component was significantly up-regulated, but the ATP-sensitive component was marginally reduced, although not significantly. These results suggest that up-regulation of the P2X component of bladder contraction seen in humans with bladder instability, and in other species models of BOO, is not mirrored in the rat, or occurs later in the pathological process of bladder hypertrophy.     

Connexin45 expression in the human obstructed detrusor muscle

Purpose  Patients with benign prostatic hyperplasia (BPH) and bladder outlet obstruction (BOO) frequently develop lower urinary tract symptoms (LUTS). To elucidate the underlying pathomechanisms we focused on altered cellular communication between detrusor cells. Methods  Bladder biopsies were collected from eight BPH patients with compensated BOO and from eight non-obstructed patients. Detrusor areas were separated by laser capture microdissection microscopy, and extracted RNA was subjected to quantitative RT-PCR for connexin43 and connexin45. Furthermore, localization of connexin45 and lysosome membrane associated protein 1 was studied by immunohistochemistry. Results  We found the human detrusor to express connexin45 rather than connexin43. Compared to controls, connexin45 expression was not significantly changed in detrusors of obstructed patients. However, connexin45 protein patterns were focally altered in obstruction. Conclusions  Our study is the first to provide evidence that connexin45-coupling of detrusor cells may be regionally impaired in patients with BOO due to BPH. The altered connexin45 coupling may contribute to LUTS.     

Adherens junctions of the human detrusor

OBJECTIVE: To immunohistochemically identify the protein composition of adherens junctions, which couple smooth muscle cells mechanically, and to confirm their decrease in different bladder dysfunctions, as studies in geriatric bladder dysfunction show fewer such junctions in patients with detrusor overactivity (DO) and bladder outlet obstruction (BOO). MATERIAL AND METHODS: Detrusor biopsies were obtained from video-urodynamically evaluated patients with neurogenic DO (NDO, 31 patients), BOO (six patients) and from six patients with stress urinary incontinence (SUI) with stable, unobstructed detrusors (serving as controls). Specimens were fixed, paraffin-embedded, sectioned, stained with a polyclonal pan-cadherin antibody, monoclonal alpha-, beta- and gamma-catenin antibodies, and a monoclonal integrin-beta1 antibody. All antibodies were known to react with proteins of adherens junctions. Two examiners unaware of sample origin evaluated the sections qualitatively and using a semiquantitative scale. The results were correlated with the patient groups. RESULTS: Specific immunohistochemical staining of pan-cadherin, alpha-, beta- and gamma-catenin could not be detected in any detrusor smooth muscle compartment, but was present in the urothelium. There was integrin-beta1 reactivity in the basement membranes of bladder smooth muscle cells in 38 of 43 detrusor biopsies. There were no differences among the three groups. CONCLUSION: The known proteins of cell-cell adherens junctions are not part of the cell-cell junctions of detrusor smooth muscle. The specific staining of integrin-beta1 indicates either the presence of cell-matrix junctions or of cell-cell junctions within the human detrusor. Further studies are needed to identify the complete protein composition of adherens junctions within smooth muscle cells.     

The detrusor muscle: an innocent victim of bladder outlet obstruction

OBJECTIVES: Benign prostatic hyperplasia (BPH) is considered a frequent cause of bladder outlet obstruction (BOO) and lower urinary tract symptoms (LUTS), although the physiopathologic mechanism through which BPH causes LUTS is not clear. Several morphologic and functional modifications of the bladder detrusor have been described in patients with BPH and could play a direct role in determining symptoms. The opinion is spreading that the enlarged prostates in patients with LUTS is nothing more than a mere bystander. Evidence has accumulated, however, supporting the role of BPH-related BOO as the direct cause determining bladder dysfunction and indirectly causing urinary symptoms. The present review addresses the bladder response to BOO, particularly focusing on the physiopathologic cascade that links obstructive BPH to bladder dysfunction. METHODS: A literature review of peer-reviewed articles has been performed, including both in vivo and in vitro studies on human tissue and animal model experiments. RESULTS: Epithelial and smooth muscle cells in the bladder wall are mechanosensitive, and in response to mechanical stretch stress caused by BOO, undergo modifications of gene expression and protein synthesis. This process involves several transduction mechanisms and finally alter the ultrastructure and physiology of cell membranes, cytoskeleton, contractile proteins, mitochondria, extracellular matrix, and neuronal networks. CONCLUSIONS: BOO is the initiator of a physiopathologic cascade leading to deep changing of bladder structure and function. Before being a direct cause of storing-phase urinary symptoms, the bladder is the first innocent victim of prostatic obstruction.     

Can urodynamic assessment of outflow obstruction predict outcome from watchful waiting?--A four-year follow-up study

0BJECTIVE: One of the most common "treatment" alternatives in suspected outflow obstruction due to bladder outlet obstruction (BOO) is watchful waiting (WW). The aim of this study was to see whether there were any differences in outcome between patients with slight, moderate or severe obstruction due to BOO as classified by transrectal ultrasound (TRUS) and urodynamics. MATERIAL AND METHODS: Thirty-seven men with lower urinary tract symptoms (LUTS) and suspected BOO were included. All of the patients were investigated by a routine investigation schedule, including TRUS and urodynamics with pressure-flow measurement (pQS) at baseline. Patients with cancer in the urinary tract, prostatitis, history of detrusor hyperreflexia (peripheral or central diseases or trauma to the nervous system affecting the bladder) and serious systemic diseases were excluded. Patients were examined at baseline, then checked again after 1 year and 4 years. Patients who did not want to continue with WW were listed as treatment failures. RESULTS: At baseline, 43.2% of the patients were urodynamically severely obstructed and 32.3% were moderately obstructed. Thirty-five per cent of the patients were found to have previously unknown detrusor hyperactivity/overactivity. The prevalence of detrusor hyperactivity/overactivity increased with BOO. After 1 year, IPSS had decreased at unchanged Qmax and postresidual volume. These findings persisted at 4 years. The failure rate increased in the more obstructed patients and was significantly higher with more severe obstruction. Complications were found in 13.5%, with no significant differences between patients with minor BOO [Detrusor Adjusted Mean PURR Factor (DAMPF) scale <42], moderate BOO (DAMPF 42-65) and severe BOO (DAMPF >65). CONCLUSIONS: In patients with severe BOO, the LUTS and failure rate increase over time. The percentage of patients with detrusor hyperactivity/overactivity was higher in the severely obstructed group. By including full urodynamics when investigating patients with BOO, it seems possible to predict the failure rate according to the patients' obstruction grade. This gives an opportunity to treat the patient with minimal invasion, and to give the individual patient a more precise prognosis if WW is preferred.     

The influence of alpha1-adrenoreceptors on neuropeptide release from primary sensory neurons of the lower urinary tract

OBJECTIVES: Adrenergic alpha(1)-receptors agonists and antagonists have been reported to increase and reduce, respectively, neurogenic inflammatory responses mediated by capsaicin-sensitive sensory neurons. However, the precise role and localization of the alpha(1)-adrenoceptors involved in these effects are not known. METHODS: We have studied in the rat whether functional alpha(1)-adrenoreceptors are expressed in primary sensory neurons, and whether they regulate neurogenic inflammation and nociceptive responses in the urinary bladder. RESULTS: The alpha(1)-adrenoreceptor agonist phenylephrine (1 micromol/l) (1) mobilized intracellular Ca(2+) in cultured lumbar and sacral dorsal root ganglia neurons, (2) caused the release of substance P (SP) from terminals of capsaicin-sensitive sensory neurons from the lumbar enlargement of the dorsal spinal cord and urinary bladder, and (3) increased plasma protein extravasation in the urinary bladder. All these effects were abolished by the alpha(1)-adrenoceptor antagonist alfuzosin (10 micromol/l). Furthermore, alfuzosin (30 microg/kg, i.v.) partially, but significantly, inhibited cyclophosphamide-induced plasma protein extravasation in the rat urinary bladder. Phenylephrine-induced Ca(2+) mobilization in cultured dorsal root ganglia neurons was exaggerated by pretreating the rats in vivo with cyclophosphamide. Finally, cyclophosphamide increased c-fos expression in the rat lumbar spinal cord. Also these in vitro and in vivo effects were inhibited by pretreatment with alfuzosin. CONCLUSIONS: Alpha(1)-adrenoceptors are functionally expressed by capsaicin-sensitive, nociceptive, primary sensory neurons of the rat urinary tract, and their activation may contribute to signal irritative and nociceptive responses arising from the urinary tract. It is possible that, at least, part of the beneficial effects of alpha(1)-adrenoceptor antagonists in the amelioration of storage symptoms in the lower urinary tract derives from their inhibitory effect on neurogenic inflammatory responses.     

The detrusor muscle cell in bladder outlet obstruction--ultrastructural and morphometric findings

OBJECTIVE: Lower urinary tract symptoms (LUTS) in elderly males are not solely caused by bladder outlet obstruction (BOO) and may be at least partly attributable to detrusor dysfunction. Urodynamically, patients may show instability, hypocontractility, BOO or combinations of these findings. These findings have been related to specific ultrastructural changes in detrusor smooth muscle cells; however, this relationship is controversial. The aim of this study was to correlate ultrastructural findings in patients with BOO with urodynamic parameters. MATERIAL AND METHODS: In 25 men with BOO verified by means of a full urodynamic evaluation, including a pressure-flow study, a detrusor biopsy was obtained. Six men without BOO served as controls. Biopsies for electron microscopy were analysed semiquantitatively and morphometrically to determine the presence of muscle cell hypertrophy, variation in intercellular distances, occurrence of abnormal cell junctions and configurations and intracellular changes. RESULTS: The only parameter which was found to relate to the degree of obstruction in BOO was an increase in intra- and interfascicular elastin, all other correlations not reaching significance. CONCLUSION: This study does not confirm a specific relationship between ultrastructural detrusor smooth muscle features and various types of BOO. Therefore ultrastructural investigation of detrusor smooth muscle cells cannot replace urodynamic evaluation in the classification of LUTS.     

Possible role of endothelin-1 in the rabbit urinary bladder hyperplasia secondary to partial bladder outlet obstruction

OBJECTIVES: Urinary bladder hypertrophy and hyperplasia are common features of bladder outlet obstruction (BOO). The urinary bladder is known to synthesize endothelin-1 (ET-1), which is a potent vasoconstrictor peptide with mitogenic properties. Using an animal model of partial BOO, we investigated the potential role of ET-1 and its receptor subtypes (ET(A) and ET(B)) in bladder smooth muscle cell (SMC) proliferation. MATERIALS AND METHODS: Partial BOO was produced in adult male New Zealand White rabbits. After 3 weeks, the bladder was removed and SMCs from the dome and bladder neck were grown using standard explant methodology. At passage 2, the cells were made quiescent and then further incubated in foetal calf serum (FCS), control age-matched rabbit serum (CRS) or partial BOO serum (BRS) in the presence or absence of ET(A)-antagonist (BQ123) or ET(B)-antagonist (BQ788). SMC proliferation was then measured 24 h later with 5-bromo-2'deoxy-uracil and by cell counting using a haemocytometer at 48 h. Immunostaining for alpha-actin was performed on detrusor and bladder neck cells to confirm the presence of smooth muscle cells. RESULTS: BQ123 and BQ788 did not influence detrusor or bladder neck SMC proliferation in FCS or CRS. However, in the presence of BRS, BQ123 and BQ788 (100 nmol/L) significantly (p = 0.008) inhibited detrusor and bladder neck SMC proliferation. Cell counts were significantly reduced from the detrusor (p = 0.03, p = 0.01 with BQ123 and BQ788, respectively) and bladder neck (p = 0.01 for both BQ123 and BQ78). CONCLUSIONS: These results suggest that ET antagonists may have a role in preventing SMC hyperplasia associated with partial BOO.     

Ultrasound assessment of detrusor thickness in men-can it predict bladder outlet obstruction and replace pressure flow study?

PURPOSE: We estimated the diagnostic accuracy of ultrasound detrusor thickness measurement for BOO and investigated whether this method can replace PFS for the diagnosis of BOO in some patients with lower urinary tract symptoms. MATERIALS AND METHODS: Detrusor thickness was measured by linear ultrasound (7.5 MHz) at a filling volume of greater than 50% of cystometric capacity in 102 men undergoing PFS for LUTS. All patients with prior treatment for bladder outlet obstruction and those with underlying neurological disorders were excluded from analysis. Detrusor thickness was correlated with PFS data. Obstruction was defined according to the Abrams-Griffiths nomogram. RESULTS: Detrusor thickness was significantly higher (p <0.0001) in obstructed (61 cases, median detrusor thickness 2.7 mm, IQR 2.4 to 3.3) compared to unobstructed (18 cases, median detrusor thickness 1.7 mm, IQR 1.5 to 2) as well as equivocal (23 cases, median detrusor thickness 1.8 mm, IQR 1.5 to 2.2) cases. A weak to medium Spearman correlation was found between detrusor thickness and PFS parameters. For a diagnosis of BOO, detrusor thickness of 2.9 mm or greater had a positive predictive value of 100%, a negative predictive value of 54%, specificity of 100% and sensitivity of 43%. ROC analysis revealed that detrusor thickness had a high predictive value for BOO with an AUC of 0.88 (95% CI 0.81-0.94). CONCLUSIONS: In men with LUTS without prior treatment and/or neurological disorders, ultrasonographically assessed detrusor thickness 2.9 mm or greater has a high predictive value for BOO and can replace PFS for the diagnosis of BOO. However, this cutoff value needs to be validated in a larger study population.     

Correlation of urinary nerve growth factor level with pathogenesis of overactive bladder

AIMS: The origin of overactive bladder (OAB), which is a leading cause of lower urinary tract symptoms, remains unknown. Nerve growth factor (NGF) is one of the neurotrophic factors which are needed for the maintenance of sensory neurons. It is known that too much expression of NGF may induce bladder hyperactivity. In this study, we explored the correlation of the level of urinary NGF with various pathogenic OAB such as idiopathic, neurogenic OAB, and bladder outlet obstruction (BOO). METHODS: The study group included 51 OAB patients. Thirteen patients (7 females and 6 males) had idiopathic detrusor overactivity (DO) without BOO, 6 female idiopathic OAB without DO (sensory urgency), 16 patients with BOO due to BPH, and 16 patients with neurogenic DO (10 due to spinal cord injury (SCI), 6 due to cerebrovascular disease (CVD)). Thirty-two patients who had normal cystometric findings (23 females and 9 males) without OAB symptoms were used as controls. Urinary NGF levels were measured by enzyme-linked immunosorbent assay technique (ELISA) and the results were normalized based on creatinine (Cr) concentration. RESULTS: The urinary NGF levels in patients with neurogenic DO due to SCI, BOO, and sensory urgency were significantly higher compared with those of normal cystometric finding patients. However, the levels of urinary NGF were not statistically significant between patients with idiopathic DO without BOO, neurogenic DO due to CVD and patients with normal cystometric findings. CONCLUSIONS: These data suggest that urinary NGF levels could serve as a basis for adjunct diagnosis of OAB.