豚鼠逼尿肌不稳定模型的建立与评估方法的改进

目的寻找一种简单、可靠的方法建立并评估豚鼠膀胱逼尿肌不稳定模型。方法成年雌性豚鼠经会阴部尿道结扎，6周后行膀胱穿刺充盈性膀胱测压，观察膀胱压力、容量变化及逼尿肌不稳定的发生情况。结果实验组逼尿肌不稳定发生率35．9％，对照组无发生，其中逼尿肌不稳定膀胱组膀胱最大压力和最大容量较对照组显著增加（P〈0．01）。结论经会阴部尿道结扎、膀胱穿刺充盈性膀胱测压是建立及评估豚鼠膀胱出口梗阻引起逼尿肌不稳定模型的一种简单、可靠的方法。     

膀胱出口梗阻时的逼尿肌不稳定（综述）

逼尿肌不稳定是造成尿频，尿急和急迫性尿失禁等症的主要原因之一，常继发于膀胱出口梗阻，在前列腺增生症中多见，与术后症状继续存在密切相关，近年，由于尿动力学技术的发展和应用，引起临床对此病的广泛关注。     

逼尿肌自身肌源性变化与逼尿肌不稳定的关系

目的:探讨逼尿肌不稳定(Detrusor instability,DI)的发病机制。方法:建立Wistar大鼠膀胱流出道梗阻(Bladder outlet obstruction,BOO)动物模型,6周后行充盈性膀胱测压分出梗阻后稳定组和不稳定组,进行离体膀胱充盈性测压、逼尿肌条机械牵拉及胆碱类药物刺激试验。结果:不稳定组膀胱充盈至出现收缩时的压力明显低于稳定组及正常对照组,收缩发生时的容积明显低于稳定组;不稳定组逼尿肌条机械牵拉至其出现收缩时的最小张力明显低于稳定组及正常对照组;不同浓度氯化氨基甲酰胆碱刺激诱发的收缩频率各组间差异无统计学意义(P<0.05)。结论:逼尿肌不稳定的发生与逼尿肌自身的兴奋性增强密切相关。     

膀胱逼尿肌不稳定研究进展

逼尿肌不稳定（detrusor instability,DI）是指在膀胱充盈时自发或诱发的逼尿肌不自主收缩,使逼尿肌出现高于15cmH2O的压力波[1]。DI可引起尿急、尿频、夜尿增多、尿失禁等下尿路症状,严重者引起肾、输尿管积水和肾功能损害,严重影响患者的生活质量。但对DI的发病机理尚未完全阐明,临床治疗效果欠佳,现就DI的研究进展做一综述.     

肾上腺素α1受体亚型与大鼠膀胱出口梗阻所致逼尿肌不稳定的关系

目的：探讨肾上腺素α1受体亚型与大鼠膀胱出口梗阻（BOO）所致逦尿肌不稳定（DI）的关系。方法：利用雄激素诱导前列腺肥大建立雄性SD大鼠膀胱出口梗阻模型,梗阻6周后行允盈性膀胱测压、离体逼尿肌条收缩实验及Western Blotting蛋白印迹实验。结果：BOO动物模型梗阻6周后逼尿肌不稳定的发生率为90％,DI组与对照组相比．排尿压力升高．（69．30±9．90）vs（49．60±8．36）cmH2O（P〈0．05）。剩残余尿量增加（0．29±0．07）vs（0,10±0．05）ml（P〈0．05）。膀胱容量增加（0．59±0．07）vs（0．23±0．05）ml（P〈0．05）。肌条收缩力升高（O．89±0．07）vs（0．43±0．05）g（P〈0．05）。α1D受体蛋白表达程度高于对照组,α1A受体表达程度未发生变化。结论：肾上腺素α1D受体主要参与到大鼠膀胱出口梗阻后逼尿肌不稳定的发生发展中。     

膀胱出口梗阻时的逼尿肌不稳定(综述)

逼尿肌不稳定是造成尿频、尿急和急迫性尿失禁等症状的主要原因之一,常继发于膀胱出口梗阻,在前列腺增生症中多见,与术后症状继续存在密切相关。近年,由于尿动力学技术的发展和应用,引起临床对此症的广泛关注。     

膀胱出口梗阻患者等待观察、药物治疗和手术治疗后的逼尿肌不稳定评价

为评价膀胱出口梗阻患者药物治疗、手术治疗或等待观察后的逼尿肌不稳定性 ,作者对 2 5 5例症状性良性前列腺增生患者进行观察。患者均完成了IPSS评价及尿动力学检查 ,其中 16 1例存在膀胱出口梗阻。 10 6例患者完成平均 2年的随访 (1～ 5年 ) ,其中包括等待观察 2 0例、药物治疗 36例 (alfuzosin2 0例、finasteride 16例 )、手术治疗 4 5例 (前列腺切开 13例、前列腺切除 32例 )。结果发现患者随访前后总的逼尿肌不稳定发生率分别为 5 2 % (5 3/ 10 1)和4 0 % (4 1/ 10 1)。等待观察组观察前后的不稳定发生率分别为 4 5 %和 5 5 % (P =0 …     

金匮肾气丸治疗良性前列腺增生症合并逼尿肌不稳定17例

目的:评价金匮肾气丸对良性前列腺增生合并逼尿肌不稳定患者的影响.方法:根据尿动力学检查,对35例良性前列腺增生症诊断为膀胱出口梗阻合并逼尿肌不稳定患者分为可多华(4 mg/d)治疗组和可多华(4 mg/d)联合金匮肾气丸(6 g)组,分别在治疗3个月时采用国际前列腺症状评分(IPSS)、储尿期症状评分(SSS)、生活质量评分(QOL)评价治疗效果.结果:两组基线特征相似,治疗3个月后联合治疗组IPSS、SSS和QOL优可多华组.结论:金匮肾气丸可减轻良性前列腺增生合并逼尿肌不稳定患者储尿期症状.     

逼尿肌不稳定对老年前列腺增生下尿路症状尿动力学参数的影响

目的探讨老年前列腺增生（BPH）下尿路症状（LUTS）伴逼尿肌不稳定（DI）患者的临床及尿动力学特点。方法对120例患者根据尿动力学检查均诊断为膀胱出口梗阻（BOO）,根据DI的存在与否分为2组,其中DI组63例,非DI组57例。对2组患者前列腺体积（VP）、国际前列腺症状评分（IPSS）、尿流率（Qmax）、残余尿（RV）、PSA和尿动力学参数进行比较。结果 DI组与非DI组年龄分别为（75.5±5.8）和（73.5±4.9）岁,IPSS分别为（28.3±5.1）和（27.9±4.9）,PSA为（4.5±1.8）和（4.2±1.6）ng/mL,Qmax为（5.6±2.8）和（6.0±3.1）mL/s,以上参数2组间无统计学意义（均P〉0.05）;DI组与非DI组VP为（78.2±25.8）mL与（55.5±22.6）mL（P=0.02）,RV为（48.5±26.8）和（140.2±57.3）mL（P=0.018）,初始尿意容量（FUR）为（95.0±25.0）和（135.0±26.0）mL（P=0.001）,最大尿意容量（MUR）为（192.5±50.0）和（328.5±58.0）mL（P=0.005）,梗阻级别为4.6±1.1和3.3±1.8（P=0.015）。结论前列腺体积大、BOO明显的患者易合并DI;DI患者尿动力学特点为膀胱敏感性增加,膀胱功能容量与残余尿量减少;尿动力学检查是准确诊断DI,指导进行临床治疗与预防的前提。     

ATP敏感钾通道在大鼠逼尿肌不稳定膀胱中的表达及变化

目的：探讨ATP敏感钾通道（KATP）与逼尿肌功能变化之间的关系。方法：根据膀胱压力容积测定结果将动物分为稳定组（29只）和不稳定组（9只）,其中稳定组分为BOO（11只）、SCI模型（9只）和对照组（9只）,通过RT-PCR技术测定逼尿肌中各型KATPmRNA表达及变化。结果：正常大鼠中逼尿肌不稳定发生率为24．3％。KATP在各组模型大鼠逼尿肌中均有表达。KATP的SUR2B亚型在BOO和SCI组逼尿肌中的表达高于正常对照组;IDI组中SUR2B的含量与正常对照组无明显差别。结论：KATP的表达异常可能是导致平滑肌细胞静息电位降低、兴奋性增高,引起逼尿肌不稳定的重要原因。     

Cystometric evaluation of bladder function in non-anesthetized mice with and without bladder outlet obstruction

PURPOSE: To develop a model for cystometric study of bladder function in the awake mouse, and to characterize urodynamically and immunohistochemically the non-obstructed and infravesically obstructed mouse bladder. MATERIALS AND METHODS: Non-obstructed Balb/CJ mice, and mice with bladder outlet obstruction after surgical, partial ligation of the urethra underwent continuous cystometry as previously described for rats. Bladders were also investigated by immunohistochemistry. RESULTS: During the period of cystometry, reproducible micturition patterns were obtained. Marked differences in the urodynamic parameters between non-obstructed and obstructed mice were revealed. In mice subjected to urethral obstruction, micturition pressure (p <0.05), threshold pressure (p <0.05), bladder capacity (p <0.001), micturition volume (p <0.001), and residual volume (p <0.05) increased significantly. There was no difference in basal pressure or compliance between non-obstructed and obstructed mice. Non-voiding bladder activity was consistently recorded in obstructed mice; both frequency and amplitude increased significantly (p <0.01). Compared with non-obstructed bladders, obstructed bladders showed hypertrophy of the bladder wall and various degrees of "patchy denervation" of the detrusor. When tested in non-obstructed mice capsaicin, prostaglandin E2 (intravesical administration) and apomorphine (subcutaneous administration) induced bladder overactivity. CONCLUSIONS: Continuous cystometry can be reproducibly performed in awake, freely moving non-obstructed mice and mice with bladder outflow obstruction. The changes induced by infravesical obstruction in mice were similar to those previously found in rats. This model may be useful for investigations of genetically modified mice.     

TAC‐302 promotes neurite outgrowth of isolated peripheral neurons and prevents bladder denervation related bladder dysfunctions following bladder outlet obstruction in rats

Aims

To evaluate the ability of TAC‐302, a cyclohexenoic fatty alcohol derivative, to enhance neurite outgrowth in cultured rat dorsal root ganglion (DRG) neurons, and the preventive effects of TAC‐302 on bladder denervation‐related storage and voiding dysfunctions in rats with bladder outlet obstruction (BOO).

Methods

Rat DRG neurons were cultured in the presence of TAC‐302. Cell numbers and neurite lengths were quantified after a 24 h culture. BOO was achieved by partial ligature of the proximal urethra in female rats. BOO rats were divided into three groups and orally treated with vehicle of 3 or 30 mg/kg TAC‐302 twice a day for 4 weeks. Cystometry was performed under conscious conditions. Immunohistochemical staining using anti‐PGP9.5 of the bladder muscle layer was performed, and the innervation area was scored.

Results

TAC‐302 significantly and dose‐dependently increased neurite outgrowth in cultured DRG neurons. BOO rats showed a decreased innervation area in the urinary bladder compared to sham‐operated rats. BOO‐induced denervation of the urinary bladder was partially prevented by oral treatment with TAC‐302. TAC‐302 significantly reduced the frequency of non‐voiding contraction (NVC) and residual urine volume (RUV) compared with the BOO vehicle group (P < 0.05). The innervation area score exhibited significant negative correlations with NVC and RUV, indicating that they increased according to the progression of denervation.

Conclusions

Our data indicate that TAC‐302 promotes neurite outgrowth in vitro. In addition, TAC‐302 prevents BOO‐induced bladder dysfunction in rats, and has a protective effect on bladder denervation.     

膀胱出口梗阻大鼠膀胱过度活动的研究

目的:建立膀胱出口梗阻大鼠模型,诱发逼尿肌不稳定(DI),研究膀胱出口梗阻伴发膀胱过度活动的病理生理学特征。方法:选择38只成年SD雌性大鼠,随机分为模型组和对照组,结扎膀胱颈部建立膀胱出口梗阻模型。建模后3、6、9、12周采用BL-410生物机能实验系统测定膀胱压,以充盈期出现DI作为膀胱过度活动存在的标准,记录并计算DI阳性率和频率、最大排尿压(MVP)、最大膀胱容量(MCC)、膀胱顺应性(BC)和剩余尿量(PVR)。用光镜观察建模不同时期膀胱组织的病理学改变。结果:模型组大鼠3、6、9、12周DI阳性率分别为37.50%、75.00%、75.00%、62.50%。MVP、MCC、BC、PVR和DI频率较对照组增高(P<0.01),第9周大鼠PVR、MVP、MCC高于第3、6和12周。不同时期病理学改变呈现出膀胱容量增加、肌层逐渐增厚和纤维化的过程。结论:膀胱出口梗阻与逼尿肌不稳定的发生具有潜在的相关性,其病理学改变和尿流动力学参数反映了膀胱的病理生理学特点。     

Benefits and limitations of animal models in partial bladder outlet obstruction for translational research

The functions of the lower urinary tract have been investigated for more than a century. Lower urinary tract symptoms, such as incomplete bladder emptying, weak urine stream, daytime urinary frequency, urgency, urge incontinence and nocturia after partial bladder outlet obstruction, is a frequent cause of benign prostatic hyperplasia in aging men. However, the pathophysiological mechanisms have not been fully elucidated. The use of animal models is absolutely imperative for understanding the pathophysiological processes involved in bladder dysfunction. Surgical induction has been used to study lower urinary tract functions of numerous animal species, such as pig, dog, rabbit, guinea pig, rat and mouse, of both sexes. Several morphological and functional modifications under partial bladder outlet obstruction have not only been observed in the bladder, but also in the central nervous system. Understanding the changes of the lower urinary tract functions induced by partial bladder outlet obstruction would also contribute to appropriate drug development for treating these pathophysiological conditions. In the present review, we discuss techniques for creating partial bladder outlet obstruction, the characteristics of several species, as well as issues of each model, and their translational value.     

A dose‐dependent dual effect of oestrogen on voiding in the male mouse?

OBJECTIVES: To explore the effect of different degrees of oestrogenization on male voiding, by treating adult castrated and 5alpha-dihydrotestosterone (DHT)-maintained male mice with different doses of oestrogens, as exposure of male mice to excessive amounts of oestrogens can cause bladder outlet obstruction (BOO); in addition, male mice lacking oestrogen receptor (ER)alpha (ERKO) or ERbeta (BERKO) were studied to assess the importance of ER subtypes. MATERIALS AND METHODS: Castrated, DHT-maintained adult mice were treated with 17beta-oestradiol (E(2); 50 and 250 microg/kg) or oestrone (E(1); 5, 50 and 500 microg/kg) daily for 10 days. Control mice were treated only with the vehicle. BERKO and ERKO mice, and their wild-type littermates used as their controls, remained untreated. Under anaesthesia, the bladder and distal urethra were exposed to record simultaneously the bladder pressure and urinary flow rate from the distal urethra. RESULTS: E(2)-treated mice showed obstructive voiding, seen as increased bladder pressure, decreased average flow rate and prolonged micturition time. This was also evident when a high dose (500 microg/kg) of E(1) was used. After treatment with a dose of 50 microg/kg, the urodynamic variables were similar to those in the control mice. Surprisingly, after treatment with a low dose (5 microg/kg) all urodynamic variables improved. There was a minor increase in the bladder pressure in BERKO mice; ERKO mice had a significantly lower urinary flow rate. CONCLUSIONS: High doses of oestrogens caused BOO in castrated, DHT-maintained male mice. A small dose of E(1) had a positive effect on voiding, suggesting that oestrogens are needed for normal male voiding. Reduced urinary flow rates in ERKO mice suggest that oestrogen effects on voiding are mediated at least partly via ERalpha.     

Role of supraspinal serotonin receptors for micturition in normal conscious rats

Serotonin (5-HT) receptors are widely distributed in the central nervous system, including several areas involved in the control of micturition reflex pathways. However, the roles of the different subtypes of 5-HT receptors are not well known. We studied in normal, conscious rats, the effects on the cystometrogram of intracerebroventricular (i.c.v.) administration of 5-HT, 8-hydroxy-2-(di-N-propylaminotetralin) (8-OH-DPAT; agonist at 5-HT(1A) receptors), alpha-methyl-5-hydroxytryptamine maleate (agonist at 5-HT(2) receptors), 2-methyl-5-hydroxytryptamine hydrochloride (agonist at 5-HT(3) receptors), and 1-(4-amino-5-chloro-2methoxyphenyl)-3-(1-n-butyl-4piperidinyl)-1-propanone hydrochloride (RS67506; agonist at 5-HT(4) receptors). Female Sprague-Dawley rats, weighing approximately 230 g, were used. A polyethylene catheter was inserted into the bladder through the dome for cystometric investigations. For administration of drugs, a catheter was implanted into the right cerebral ventricle. Three days after implantation of the bladder catheter, continuous cystometry was performed. Administration of 5-HT (6 nmol/kg i.c.v.), 8-OH-DPAT (6 nmol/kg), alpha-methyl-5-hydroxytryptamine maleate (6 nmol/kg), or RS67506 hydrochloride (6 nmol/kg) significantly (P < 0.05) increased micturition pressure and decreased bladder capacity and micturition volume. The effects increased in a dose-dependent manner (18, 60 nmol/kg). Intracerebroventricular administration of 2-methyl-5-hydroxytryptamine hydrochloride (60 nmol/kg) caused no change in the cystometric parameters. The results suggest that in normal conscious rats, at the supraspinal level, 5-HT (via 5-HT(1A), 5-HT(2), and 5-HT(4) receptors) can enhance the micturition reflex induced by bladder filling. Whether this means that 5-HT(1A), 5-HT(2), and 5-HT(4) receptors can be targets for drugs meant for treatment of bladder hyperactivity, should be explored.     

Cholinergic and purinergic contribution to the micturition reflex in conscious rats with long-term bladder outlet obstruction

The urethra of female Wistar rats was partially obstructed for 15 weeks. The effects of atropine (1 mg/kg i.v.), suramin (100 mg/kg i.v.), and a combination of atropine and suramin on the peak micturition pressure (MP) were compared during cystometry in conscious rats controls or subjected to outlet obstruction. On the isolated bladder dome, we studied the inhibitory effect of 1 micromol/L atropine, 1 mmol/L suramin, and the combination of the two drugs on contractions induced by electrical field stimulation (EFS). We studied also the contractile response to 80 mmol/L KCl and the concentration-response curves to noradrenaline, phenylephrine, and carbachol on the bladder dome and bladder neck and alpha, beta-methylene adenosine triphosphate on the bladder dome. In conscious rats, the MP, bladder capacity, and micturition volume were significantly higher in obstructed rats than in controls. Suramin induced the same inhibition in the two groups of animals (-30.7 +/- 13.3% in controls and -29.2 +/- 8.5% in obstructed rats). Atropine decreased the MP, but this effect was twofold greater in obstructed animals (-28.1 +/- 3.1% and -65.1 +/- 6.9% in control and obstructed animals, respectively). However, the combined effect of atropine and suramin was additive in controls but not in obstructed (-56.7 +/- 5.4% and -55.9 +/- 9.4%, respectively). Similar results were obtained in vitro using 1 micromol/L atropine and 1 mmol/L suramin. In the obstructed bladder dome and bladder neck, we found a great reduction in KCl- and carbachol-induced contractility but no difference in the response to EFS. Responses to noradrenaline and phenylephrine were moderately reduced in the bladder neck only, whereas responses to alpha, beta-methylene adenosine triphosphate in the bladder dome were not reduced except at the concentration of 300 micromol/L. We conclude that long-term obstruction in rats could induce cholinergic nerve fiber proliferation as suggested by the decrease in M(3) muscarinic receptor contractility (desensitization) and by a greater sensitivity of the MP to atropine.