Phosphodiesterase 5 in the female pig and human urethra: morphological and functional aspects

OBJECTIVE: To characterize the distribution of phosphodiesterase 5 (PDE-5), cGMP and cGMP-dependent protein kinase I (PKG1), and to evaluate the effect of pharmacological inhibition of PDE-5 in isolated preparations of pig and human urethra, as the nitric oxide (NO)/cGMP pathway generates the main inhibitory signals to reduce resistance in the bladder outlet and urethra during emptying of the bladder. MATERIALS AND METHODS: After obtaining ethics committee approval, urethral specimens were obtained from three female patients during cystectomy, and from young female pigs. The specimens were prepared for immunohistochemical investigations and for functional studies in organ baths. Effects of sildenafil, vardenafil and tadalafil (1 nm to 30 microm) were studied in l-noradrenaline (1 microm)-activated or spontaneously contracted preparations, and on relaxations induced by electrical-field stimulation (EFS). Levels of cGMP were determined by radioimmunoassay. RESULTS: After stimulation with the NO donor, DETA NONO-ate (1 mm), there was greater cGMP-immunoreactivity (IR) in urethral and vascular smooth muscles. There was a wide distribution of cGMP- and vimentin-positive interstitial cells between pig urethral smooth muscle bundles. There was also cGMP-IR within NO-synthase-IR endothelium. There was PDE-5 IR within the urethral and vascular smooth muscle cells, but also in vascular endothelial cells that expressed cGMP-IR. In pig and human sections, there was strong PKG1-IR in alpha-actin-IR urethral smooth muscle cells that also contained IR for cGMP. Sildenafil, vardenafil and tadalafil caused mean (sem) concentration-dependent relaxations of the pig urethra which, at 30 microm, were 80 (3)% (11 samples), 81 (5)% (12 samples) and 64 (4)% (10 samples) of the spontaneous tone. The relaxation of L-noradrenaline-contracted female human urethra was 100% in response to 10 microm sildenafil, and 85 (15)% and 47 (13)% for 30 microm of vardenafil and tadalafil, respectively (three samples). Vardenafil or sildenafil (30 microm) doubled cGMP levels in pig specimens. There were no effects on cGMP levels with tadalafil. EFS (1-32 Hz) caused l-NG-nitroarginine-sensitive relaxations of pig urethral muscle that were increased in amplitude and duration by PDE-5 inhibition. At 0.1 microm, sildenafil, vardenafil or tadalafil significantly prolonged the mean (sem) duration of the relaxation at 4 Hz by 55 (19)%, 45 (14)% and 51 (12)%, respectively. CONCLUSIONS: PDE-5-, cGMP- and PKG1-IR is widely distributed in human and pig urethral tissues. Nerve-induced relaxations of urethral preparations were enhanced at low concentrations of sildenafil, vardenafil and tadalafil, whereas there were direct smooth muscle-relaxant actions of the PDE-5 inhibitors at high concentrations. Inhibition of PDE-5 might be an interesting option to facilitate cGMP-mediated relaxation of the outflow region.     

Contractile properties of the proximal urethra and bladder in female pig: morphology and function

AIMS: To compare the contractile properties of proximal urethral and bladder muscle of the female pig. MATERIALS AND METHODS: In two proximal segments (I and II) of the urethra, small muscle bundles were excised to measure the force-length (maximum force) and the force-velocity (unloaded shortening velocity) relation using the stop-test. The rate of force development was calculated using phase plots. Contractile properties of urethral and bladder segments were statistically compared using the Mann-Whitney U-test. Immunohistochemical staining of whole circumference urethral cross sections was used to identify the location of smooth and striated muscle fibres. RESULTS: On isometric force development, the urethral muscle bundles revealed a fast ( approximately 0.5 sec) and a slow ( approximately 2.1 sec) time constant, whereas in bladder only a slow ( approximately 2.3 sec) component was measured. On average, isometric force was highest in bladder. The length range over which force was produced was smallest in urethral segment II, followed by urethral segment I and finally bladder. The unloaded shortening velocity was 0.15, 0.25 and 0.35 1/sec, respectively. Histological preparations showed that smooth as well as striated muscle was present in proximal urethra. In urethral muscle bundles, spontaneous contractions were measured with a frequency of 0.4 Hz. CONCLUSIONS: Differences in contractility found between urethra and bladder may be ascribed to the presence of striated muscle in the proximal urethra. The regulation of tone and spontaneous contractions may be part of the continence mechanism in the female pig urinary tract.     

The anatomy of stress incontinence: magnetic resonance imaging of the female bladder neck and urethra

Clinical, urodynamic, radiological and endoscopic evaluations as well as operative results on more than 800 cases of stress incontinence treated at our medical center have led to a better understanding of the pathophysiology of female stress incontinence. We attempt to correlate these physiological concepts with information obtained from magnetic resonance images of the paraurethral and bladder neck areas in patients with known stress incontinence and normal controls. All magnetic resonance images were compared to cadaver step sections of the female pelvis. Normal controls without stress incontinence were used to define normal anatomy by magnetic resonance imaging. Etiology of incontinence was divided into either intrinsic urethral damage or anatomical malposition of an intact sphincteric unit. Our findings not only provide valuable support to basic concepts of the pathophysiology of stress incontinence but also help to establish normal findings of female paraurethral and bladder neck anatomy as seen by magnetic resonance imaging.     

Malignant lymphoma of the bladder and female urethra

Primary malignant non-Hodgkin's lymphomas account for 0.4% of malignant neoplasms arising in the bladder and female urethra, but do not comprise a uniform group, and three subgroups can be identified which account for a majority of cases. The most common is a low-grade B-cell lymphoma similar to neoplasms arising in the mucosa-associated lymphoid tissue at other sites — so-called MALTomas. These generally display indolent behavior. A second group accounting for approximately one-fifth of cases is composed almost entirely of large lymphoid cells, and these tumors have a poor prognosis. A third possible group comprises only a few patients who present with diffuse thickening of the bladder wall, and have a poor prognosis. The authors present a new case which suggests that this latter group may be of T-cell origin. In addition to these three subtypes, others no doubt await recognition. The different forms of primary lymphoma appear to require different treatments, and some guidelines are proposed.     

The epithelium in the female urethra: a quantitative study

Histological sections were prepared from 8 regions along the length of the urethra in 16 women 19 to 82 years old. The epithelium was examined under the light microscope at 4 points in each region and the type of epithelium was classified. Our results indicate that the human female urethra is lined by stratified squamous, pseudostratified columnar and, occasionally, transitional epithelium. There is a gradual change from squamous to columnar epithelium with advancing age. More squamous epithelium is present at the distal end of the urethra.     

经尿道膀胱颈内切开术治疗女性膀胱颈梗阻的疗效观察

目的:评估经尿道膀胱颈内切开术治疗女性原发性膀胱颈梗阻(PBNO)的长期疗效。方法:56例女性患者通过排泄性膀胱尿道造影及尿动力学检查确诊为PBNO,在膀胱颈上选取2点及10点位置,所有患者行经尿道膀胱颈内切开术。结果:术后随访6~72个月(平均26.2个月)。56例接受手术的患者中47例(83.9%)术后恢复良好,未见严重并发症。随访过程中,平均国际前列腺症状评分(IPSS)由21.2降至7.6(P<0.05),生活质量评分(QOL)由4.2降至2.3(P<0.05),最大尿流率(Q_max)由8.63ml/s增至17.36ml/s(P<0.05),残余尿量(PVR)由106.32ml降至21.46ml(P<0.05),最大尿流率时逼尿肌压力(Pdet at Q_max)由68.42cmH_2O降至19.86cmH_2O(1cmH_2O=0.098kPa,P<0.05)。术后出现的并发症有血尿、二次行膀胱颈内切开术、压力性尿失禁、尿道狭窄。所有这些并发症按Clavien分类评估为Ⅲa级。3例(5.3%)术后出现出血,经延长尿管留置时间、膀胱冲洗治愈,均未输血治疗;4例(7.1%)出现压力性尿失禁,行经阴道无张力尿道中段吊带术后恢复;4例(7.1%)出现尿道狭窄,间断尿道扩张后好转。结论:PBNO不常见,排泄性膀胱尿道造影及尿动力学检查可确诊,通过经尿道膀胱颈内切开术治疗安全有效。在膀胱颈的2点和10点方向仔细地、足够深度地行颈内切开可以保证手术的成功。     

Trans-abdominal ultrasound shear wave elastographyfor quantitative assessment of female bladder neck elasticity

Introduction and hypothesis

Disorders of micturition result from a wide variety of conditions and evaluation often involves multiple diagnostic modalities. However, the sensitivity and specificity of these techniques are highly variable and may not always yield a diagnosis. Novel imaging techniques such as ultrasound shear wave elastography may help to improve diagnostic accuracy.

Methods

Continent women were recruited from outpatient gynecology offices from a tertiary medical system. Participants underwent ultrasound evaluation with measurement of the shear wave velocity (SWV) of the bladder neck (BN). SWV was used to determine the Young’s modulus of the bladder neck. The median bladder neck stiffness was calculated and univariate and step-wise and backward multivariate logistic regression analyses were used to identify significant patient characteristics associated with bladder neck stiffness above or below the median.

Results

Fifty-seven women underwent SWE of the bladder; 12 were excluded, and 45 were included in the analysis. The median bladder neck stiffness of the study population was 22 (17.1–28.2) kPa. Age greater than 45 years was associated with a bladder neck stiffness above the median, OR 8.39, p?<?0.001. Having no vaginal deliveries was also associated with a bladder neck stiffness greater than 22 kPa, unadjusted OR 4.76 (95 % CI 1.41–20.0, p?=?0.012). Bladder volume and bladder neck thickness were not significantly associated with bladder neck stiffness above or below the median.

Conclusion

Trans-abdominal shear wave elastography can be used to quantitatively assess bladder neck stiffness. This technique may potentially be useful for evaluating chronic urinary retention.

     

Management of the devastated posterior urethra and bladder neck: refractory incontinence and stenosis

Stricture of the proximal urethra following treatment for prostate cancer occurs in an estimated 1-8% of patients. Following prostatectomy, urethral reconstruction is feasible in many patients. However, in those patients with prior radiation therapy (RT), failed reconstruction, refractory incontinence or multiple comorbidities, reconstruction may not be feasible. The purpose of this article is to review the evaluation and management options for patients who are not candidates for reconstruction of the posterior urethra and require urinary diversion. Patient evaluation should result in the decision whether reconstruction is feasible. In our experience, risk factors for failed reconstruction include prior radiation and multiple failed endoscopic treatments. Pre-operative cystoscopy is an essential part of the evaluations to identify tissue necrosis, dystrophic calcification, or tumor in the urethra, prostate and/or bladder. If urethral reconstruction is not feasible it is imperative to discuss options for urine diversion with the patient. Treatment options include simple catheter diversion, urethral ligation, and both bladder preserving and non-preserving diversion. Surgical management should address both the bladder and the bladder outlet. This can be accomplished from a perineal, abdominal or abdomino-perineal approach. The devastated bladder outlet is a challenging problem to treat. Typically, patients undergo multiple procedures in an attempt to restore urethral continuity and continence. For the small subset who fails reconstruction, urinary diversion provides a definitive, “end-stage” treatment resulting in improved quality of life.     

In vitro alpha-adrenoceptor autoradiography of the urethra and urinary bladder of the female pig, cat, guinea-pig and rat

OBJECTIVE: The aim of this study was to investigate the distribution of alpha1- and alpha2-adrenoceptors in the urethra and urinary bladder of the female pig, cat, guinea-pig and rat. MATERIALS AND METHODS: The binding distributions of an alpha1-adrenoceptor ligand (3H-prazosin) and an alpha2-adrenoceptor ligand (3H-rauwolscine) were determined using in vitro autoradiography. Autoradiograms were analysed by combining computer-based image analysis and light microscopy. RESULTS: In the pig, guinea-pig and rat urethra 3H-prazosin binding was highest in the muscle layer. In the cat urethra 3H-prazosin binding could not be analysed due to a negative chemography artefact. In the pig, cat and guinea-pig urethra 3H-rauwolscine binding was highest in the urothelium, followed by the sub-mucosa, with low levels in muscle. Little 3H-rauwolscine binding was observed in the rat urethra. In the urinary bladder of all species 3H-prazosin binding was low. In the rat bladder, binding was higher in the trigone than in the dome. In the pig, cat and guinea-pig bladder 3H-rauwolscine binding was highest in the mucosa. with little binding in muscle or lamina propria. In the rat bladder, there was little binding and no regional differences. CONCLUSIONS: Alpha1-adrenoceptors were predominantly located in urethral smooth muscle, indicating their contractile importance in maintaining continence. Alpha2-Adrenoceptors were present in the urethral submucosa and bladder mucosa, but not in muscle, suggesting a role in regulation of blood flow, urethral lubrication and tumescence, but not in contraction.     

女性早期尿道癌膀胱黏膜尿道重建术的探讨(会议征文选登)

目的:探讨应用膀胱黏膜重建女性尿道治疗女性尿道肉阜早期癌变的疗效。方法:对10例女性尿道肉阜早期癌变患者行一期膀胱黏膜尿道重建术,并作术前、术后6个月及术后1年最大尿流率测定。结果:10例均一期成形,术后随访1-9年,排尿正常,无肿瘤复发,无尿失禁及其他并发症,术前、术后6个月及术后1年最大尿流率测定差异有统计学意义(P(0.05)。结论:对于女性尿道肉阜早期癌变及早期原发性女性尿道癌患者,应用膀胱黏膜尿道一期重建术是可行的治疗方法,具有简单、安全、有效、并发症少等优点。     

Reconstruction of bladder neck and prostatic urethra. Clinical experience with bladder flap

The authors have utilized the bladder-flap procedure in 16 patients from 1967 to 1972. The technique is detailed, and complications and long-term follow-up results are given.     

经尿道电切术治疗女性膀胱颈梗阻12例

目的探讨经尿道电切治疗女性膀胱颈梗阻的疗效。方法对12例女性膀胱梗阻患者行径尿道膀胱颈电切术治疗,年龄51±13岁,病程3个月-5年,尿流率3.8±11.4ml／s,残余尿200-800ml术后随诊6个月以上。结果手术均获成功,手术时间15-50min,平均25min,术中出血〈20ml。12例患者排尿症状评分,最大尿流率平均18ml／s,残余尿均〈50ml。最大尿流率、残余尿量等均较术前显著改善,随访无尿失禁、尿瘘发生。结论经尿道电切术治疗女性膀胱颈梗阻疗效显著,并发症少。