In vivo inhibitory effects of stimulation at the central end of the pelvic nerve severed from urinary bladder on urinary bladder contraction in rats

Two- or five-Hz electrical stimulation of the central end of the left pelvic nerve severed from the urinary bladder in rats inhibited bladder contraction induced by intravesical infusion of Tyrode's solution. Inhibition of bladder motility by 2-Hz nerve stimulation appeared after pretreatment with strychnine (0.3 mg/kg, i.v.), naloxone (1 mg/kg, i.v.) and picrotoxin (1 mg/kg, i.v.). Hypogastric nerve stimulation, however, did not affect bladder contraction. These results suggest the presence of an inhibitory mechanism on the pelvic motoneuron activated by contralateral pelvic nerve stimulation in rats.     

Effects of various drugs on bladder function in conscious rats

In the present study, we attempted to evaluate the effects of various intravenous administered drugs, which had been shown to influence bladder function in anesthetized animals, on the cystometrogram in conscious rats placed in a restraining cage. Thiopental, diazepam, baclofen, clonidine and flavoxate, considered to act on the micturition center in the brain stem, hardly increased bladder capacity (time to micturition in cystometrogram) in conscious rats, but morphine, indomethacin and lidocaine, considered to act on the micturition center in the sacral cord or bladder mechanoreceptors, increased it. In a chronic conscious rat, histopathological findings show that the bladder tissue at 2 days after implantation of the catheter to the bladder showed experimental cystitis characterized by severe edema in the submucosa and an increase in prostaglandin E2 content, which is thought to stimulate directly and/or indirectly the capsaicin-sensitive sensory fiber in the afferent branch of the micturition reflex, and there was hyperreflexia characterized by decreases in both bladder capacity and urine volume. In conclusion, cystometrography in conscious rats placed in a restraining cage is thought to be a useful model for evaluating the true effect of a newly developed agent on bladder function.     

Effects of various drugs on bladder function in conscious restrained-denervated rats placed in a restraining cage and produced by transection of the hypogastric nerve

We evaluated the effects of various intravenously administered drugs, which had been shown to influence bladder function in anesthetized and/or conscious rats, on the cystometrogram in conscious restrained-denervated rats (produced by transection of the hypogastric nerve) placed in a restraining cage in comparison to those in conscious restrained-intact rats (with the hypogastric nerve intact) placed in a restraining cage. The bladder capacity in the restrained-denervated rats was smaller than that in restrained-intact rats and did not change when they were transferred to a wide cage, but the bladder capacity of the restrained-intact rats decreased following transfer to the wide cage. Therefore, the activity of the hypogastric nerve in conscious rats appears to be stimulated by restraint. Atropine suppressed the amplitude of the micturition contraction (time to micturition in the cystometrogram). In the restrained-denervated rats, thiopental and indomethacin increased the bladder capacity at almost the same doses as those in restrained-intact rats, but it took a higher dose of morphine to increase the bladder capacity than in restrained-intact rats. These findings suggest that cystometrography in restrained-denervated rats is a useful method for evaluating the effect of a newly developed agent on bladder function without any influence from the hypogastric nerve.     

Effects of adrenergic alpha2-receptor agonists on urinary bladder contraction in conscious rats

We investigated the effects of the adrenergic alpha2-receptor agonists clonidine, oxymetazoline and tizanidine on bladder contractions induced by infusing fluid into the bladders of conscious male rats. I.v. clonidine and oxymetazoline (both 0.01 to 0.1 mg/kg) caused bladder hyperactivity, expressed by shortening of the intercontraction interval. Tizanidine (0.1 mg/kg, i.v.) caused slight shortening of the intercontraction interval. The rank order of potency was clonidine = oxymetazoline > tizanidine. Intrathecal (i.t.) injection of 10 microg clonidine and oxymetazoline, and intracerebroventricular (i.c.v) injection at 15 microg, produced almost the same pattern of bladder hyperactivity as that observed after i.v. injection of these drugs (0.03 mg/kg, i.v.). For all three administration routes of clonidine and oxymetazoline, i.v. idazoxan (0.3 mg/kg) exerted an inhibitory effect on the bladder hyperactivity induced by these drugs, except i.c.v injection of oxymetazoline. I.t. phenylephrine (30 microg) did not change the intercontraction interval. Although i.c.v. phenylephrine (15 microg) shortened the intercontraction interval, the potency was weaker than those of i.c.v. clonidine and oxymetazoline (15 microg). These results suggest that clonidine and oxymetazoline cause bladder hyperactivity by acting at adrenergic alpha2 receptors in the micturition centers of the lumbosacral and supraspinal regions.     

雄性大鼠盆神经损伤神经源性膀胱动物模型的建立

目的建立盆神经损伤后神经源性膀胱的大鼠模型,研究引起神经源性膀胱的相关因素。方法将 16只雄性 SD大鼠采用随机数字表法分为神经损伤组和假手术组,每组 8只,神经损伤组损伤双侧盆神经,假手术组仅显露神经但不做处理。 4周后行膀胱功能检测,并留取膀胱组织行 Masson染色及 VAChT阳性神经纤维免疫荧光染色。结果术后 4周,神经损伤组大鼠膀胱质量( 123.6±16.8)mg较假手术组( 87.2±11.2)mg显著增加( P＜0.05)。神经损伤组大鼠膀胱最大容量( 3.45±0.45)mL较假手术组( 1.46±0.11)mL显著增加( P＜0.05)。神经损伤组大鼠膀胱逼尿肌收缩力明显下降,最大排尿压峰值为( 12.1±6.5) mmHg,明显低于假手术组( 42.9±10.5)mmHg(P＜0.05)。 Masson染色示神经损伤组大鼠膀胱壁组织中平滑肌含量减少,胶原纤维增生明显,其胶原占比( 19.75±5.46)%显著高于假手术组( 9.95±3.25)%,(P＜0.05)。免疫荧光结果显示神经损伤组膀胱壁内 VAChT阳性神经纤维占比( 7.46±1.68)%较假手术组( 12.67±3.24)%显著减少( P＜0.05)。结论损伤大鼠双侧盆神经可成功建立神经源性膀胱动物模型,表现为膀胱逼尿肌纤维化, VAChT阳性神经纤维减少及排尿功能受损。     

Effects of central nervous system-acting drugs on urinary bladder contraction in unanesthetized rats

We studied the effects of drugs on urinary bladder contraction in unanesthetized (UA) rats using the same method as that previously employed to investigate similar effects in urethane and alpha-chloralose-anesthetized (A) rats. The surgical procedure was performed under halothane anesthesia, and after the recovery, the rats were restricted in a Ballman cage during the experiment. The pattern of the cystometrogram obtained in UA rats was very similar to that in A rats, and almost the same pattern was maintained for at least three hours. Baclofen (10 mg/kg, i.p.), morphine (10 mg/kg, i.p.) and pentobarbital (20 mg/kg, i.p.) completely inhibited the bladder contraction at doses only double those at which the same drugs inhibited the bladder contraction in A rats when i.v. injected. When the bladder pressure rose almost to the level of the peak pressure existing before injection of these drugs, the instilled solution leaked from the penis. On the other hand, even after injection of diazepam (5 mg/kg, i.p.) at a dose five times greater than the minimum amount necessary for complete inhibition of bladder contraction in A rats, the bladder contraction accompanying micturition continued in UA rats. It appears that the inhibitory effect of diazepam on bladder contraction in rats is potentiated by anesthesia.     

经尿道膀胱肿瘤电切术后不同药物膀胱灌注化疗对50例浅表性膀胱癌患者疗效及生存预后的影响

目的：探讨经尿道膀胱肿瘤电切术后不同药物膀胱灌注化疗对浅表性膀胱癌患者的疗效及生存预后的影响。方法：回顾性分析我院收治的浅表性膀胱癌患者100例,所有患者均给予常规尿道电切切除术治疗,依据治疗方法分为对照组（术后给予40 mg丝裂霉素化疗治疗）和观察组（术后给予30 mg吡柔比星化疗治疗）各50例,采用ELISA检测血清血管内皮生长因子（VEGF）、成纤维细胞生长因子（FGF）、基质金属蛋白酶-9（MMP-9）水平,随访3年,统计分析所有患者治疗前后VEGF、FGF、MMP-9水平、不良反应、复发和生存情况。结果：治疗后,观察组患者血清VEGF、FGF、MMP-9水平明显低于对照组（P＜0.05）;对照组和观察组患者不良反应发生率无显著性差异（P＞0.05）;观察组患者0.5、1、2、3年累积生存率明显高于对照组,前者复发率明显低于后者（P＜0.05）。结论：经尿道膀胱肿瘤电切术联合吡柔比星膀胱灌注化疗可有效减弱膀胱癌血管新生及癌细胞侵袭等恶性生物学行为,减少患者术后复发和改善生存预后,且无增加不良反应发生的风险。     

Effects of antimuscarinic drugs on both urinary frequency and cognitive impairment in conscious, nonrestrained rats.

Recent studies indicate a risk of learning and memory impairments when patients with senile dementia are treated with antimuscarinic drugs. In this study, we compared the effectiveness of propiverine hydrochloride (propiverine) and oxybutynin chloride (oxybutynin) on the increased urinary frequency and cognitive impairment induced by nucleus basalis magnocellularis (nBM) lesioning in conscious and nonrestrained rats. For examination of bladder function, nBM-lesioned rats were given total parenteral nutrition regimens for 8 days. Propiverine administered orally at 0.3, 3 and 30 mg/kg on the postoperative day 7 significantly lessened the increase in the frequency of voiding caused by the nBM lesion, whereas oxybutynin administration did not show any improvement at 0.1 or 1 mg/kg but did so at 10 mg/kg. To examine the memory impairment, we trained nBM-lesioned rats in an 8-arm radial maze task for 20 days and then evaluated the effectiveness of oral drug administration on 19th and 20th radial maze performance. The higher rate of errors caused by nBM lesioning was significantly aggravated by oxybutynin at 30 and 100 mg/kg. Propiverine showed slight aggravation of errors, but with no statistical significance at any dose, 30, 100 or 300 mg/kg. These results suggest that propiverine has comparatively less effect on the cognitive impairment than oxybutynin.     

Role of supraspinal tachykinins for micturition in conscious rats with and without bladder outlet obstruction

In order to clarify the role of supraspinal tachykinins in volume-induced micturition and in bladder hyperactivity secondary to bladder outlet obstruction, conscious, normal, female Sprague-Dawley rats were investigated cystometrically before and after intracerebroventricular administration of RP 67,580, a selective antagonist of neurokinin (NK)-1 receptors and/or SR 48,968, a selective antagonist of NK-2 receptors. In normal rats, RP 67,580 or SR 48,968, at a dose of 2 nmol, caused no marked changes in cystometric parameters. Higher doses (up to 20 nmol) caused dose-dependent decreases in micturition pressure and increased bladder capacity, micturition volume and residual urine. A combination of the two drugs, each at a dose of 2 nmol, significantly decreased micturition pressure and increased bladder capacity. In rats with bladder outlet obstruction, the antagonists suppressed micturition dose-dependently, producing urinary retention in two out of eight rats already at a dose of 2 nmol. At a dose of 20 nmol, dribbling incontinence, due to urinary retention, was seen in five out of ten rats. A combination of the two drugs (2 nmol of each drug) caused urinary retention in three out of nine animals and significantly increased bladder capacity, micturition volume and residual volume. The results suggest that outflow obstruction in rats increases the effects of tachykinins in supraspinal structures involved in micturition, and that antagonism of supraspinal NK-receptors may depress the micturition reflex. Whether or not this implies that supraspinal NK-receptors can be targets for drugs aimed for inhibiting bladder hyperactivity in humans should be explored.     

Emerging drugs for the treatment of erectile dysfunction

Introduction: Erectile dysfunction adversely affects the lives of millions of men, and is the most commonly treated sexual disorder today. The erectile process has been extensively investigated, with major advances made in elucidating many of the complex molecular pathways involved. These advances have allowed researchers to design and study drug formulations that target various aspects of this complex process. The initial culmination of this research was the introduction of phosphodiesterase 5-inhibitors. While effective in many patients, they are not satisfactory for all afflicted men. As a result, researchers are developing novel drugs that target different molecular pathways.

Areas covered: The paper will review these pathways, and the potential agents that target them. More specifically, first dopaminergic and melanocortin receptor agonists that act centrally will be covered. Then, the paper will examine the “second-generation” phosphodiesterase 5-inhibitors, soluble guanylate cyclases, rho-kinase inhibitors, and maxi-k channel activators that act peripherally.

Expert opinion: Most of these novel drugs have yet to reach Phase III studies. However, it is likely that in years to come, patients will be selectively treated with these novel agents as a monotherapy or in combination with others acting in a synergistic manner.     

Contractility of urinary bladder and vas deferens after sensory denervation by capsaicin treatment of newborn rats.

1. Capsaicin, a selective sensory neurotoxin, was given to newborn rats and at the age of 3 months the contractile activity of the urinary bladder detrusor muscle and vas deferens evoked by either electrical field stimulation (EFS) or exogenous adenosine 5'-triphosphate (ATP) and carbachol (urinary bladder), or ATP and noradrenaline (vas deferens) were tested. 2. EFS of the urinary bladder evoked contractions which consisted of cholinergic and purinergic components, since they could be partially blocked by either the muscarinic cholinoceptor antagonist, atropine (0.3 microM) or by desensitization of P2x-purinoceptors with alpha,beta-methylene ATP (10 microM). In capsaicin-treated rats, contractions of the urinary bladder evoked by EFS were significantly larger than those of control (vehicle-treated) animals, and this difference remained after the purinergic component of the contractions was blocked by desensitization of P2x-purinoceptors with alpha,beta-methylene ATP. However, when the cholinergic component of the contractions was blocked with atropine, the difference between the groups at 8 Hz and 16 Hz was abolished; EFS caused significantly larger contractions of the capsaicin-treated rat bladder only at frequencies of 2 Hz and 4 Hz. 3. EFS evoked contractions of the vas deferens consisted of adrenergic and purinergic components since they could be partially blocked by either the alpha-adrenoceptor antagonist, phentolamine (3 microM) or by alpha,beta-methylene ATP (10 microM). The contractions of the vas deferens were significantly larger than in the capsaicin-treated rats only at a frequency of 16 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)     

Development of a model for nerve agent inhalation in conscious rats

Abstract

This study characterizes the development of a head-out inhalation exposure system for assessing respiratory toxicity of vaporized chemical agents in untreated, non-anesthetized rats. The organophosphate diisopropyl fluorophosphate (DFP) induces classical cholinergic toxicity following inhalation exposure and was utilized to validate the effectiveness of this newly designed inhalation exposure system. A saturator cell apparatus was used to generate DFP vapor at 9750, 10?950, 12?200, 14?625 and 19?500?mg?×?min/m³ which was carried by filtered nitrogen into a glass mixing tube, where it combined with ambient air before being introduced to the custom-made glass exposure chamber. Male Sprague-Dawley rats (250–300?g) were restrained in individual head-out plethysmography chambers, which acquired respiratory parameters before, during and after agent exposure. All animals were acclimated to the exposure system prior to exposure to reduce novel environment-induced stress. The LCt₅₀, as determined by probit analysis, was 12?014?mg?×?min/m³. Weight loss in exposed animals was dose-dependent and ranged from 8 to 28% of their body weight 24?h after exposure. Increased salivation, lacrimation, urination, defecation (SLUD) and mild muscular fasciculation were observed in all DFP-exposed animals during and immediately following exposure. In all exposed animals, DFP vapor produced significant inhibition of acetylcholinesterase (AChE) activity in cardiac blood, bronchoalveolar lavage fluid (BALF), whole brain and lung tissue as well as alterations in tidal volume and minute volume. These studies have provided valuable information leading to the initiation of studies evaluating inhalational toxicity and treatments following exposure to the more lethal and potent chemical warfare nerve agents.     

A new method for producing urinary bladder hyperactivity using a non-invasive transient intravesical infusion of acetic acid in conscious rats

INTRODUCTION: Animal models that closely resemble the pathophysiology of human overactive bladder are important for evaluating novel therapeutics to treat the disorder. We established a non-invasive hyperactive bladder model that is sensitive to anti-muscarinic drugs and without bladder inflammation. METHODS: Acetic acid solution was infused into the bladder for 5 min via the urethral orifice without any surgical procedures under isoflurane anaesthesia. After washing the bladder with saline, voiding frequency (VF) and total urine volume were determined for 9 h under conscious conditions. RESULTS: Infusion of a 0.5% acetic acid solution caused a significant increase in VF, without influencing total urine volume or inducing significant histopathological inflammatory alterations in the bladder urothelium. Oral administration of oxybutynin (3 and 10 mg/kg) significantly ameliorated increases in VF induced by 0.5% acetic acid. Infusion of 0.75% acetic acid induced intensive urinary inflammation and a decrease in total urine volume as well as an increase in VF. Oral treatment with oxybutynin (10 mg/kg) did not significantly improve the increased VF due to 0.75% acetic acid. Acetic acid (0.5%) infusion evoked bladder hyper-responsiveness whether applied at night or during the day. However, VF was increased more by the nighttime application of acetic acid, while there were no significant differences in basal levels of VF between daytime and nighttime. DISCUSSION: In this study, the non-invasive rat urinary hyperactive bladder model indicated minimizes the secondary effects of experimental procedures such as surgical operations and anesthesia on bladder function and is sensitive to oxybutynin. Thus, the model may be useful for investigating novel therapeutics for OAB treatment.     

经尿道前列腺电切术后膀胱颈挛缩的诊治体会

目的探讨经尿道前列腺电切术(TURP)后膀胱颈挛缩的病因和手术方法。方法对35例膀胱颈挛缩患者的临床资料进行回顾性总结分析。结果经尿道行膀胱颈后唇、术后残留前列腺组织电切术或用冷刀切开颈部换用电切刀切除瘢痕组织,术后3个月随访32例,症状均改善或消失。结论经尿道腔内治疗TURP术后膀胱颈挛缩是一种安全有效的方法。     

经尿道前列腺电切术后膀胱颈挛缩的诊治

目的 探讨经尿道前列腺电切术(TURP)后膀胱颈挛缩(BNC)的诊断和治疗方法.方法 对12例发生膀胱颈挛缩的患者的临床资料进行回顾性总结分析.结果 经尿道行膀胱颈后唇切除,冷刀切开膀胱颈部,再换用电刀切除疤痕组织.术后平均随访12个月,症状均明显改善或消失.结论 经尿道腔内治疗TURP术后BNC是一种安全有效的方法.     

Different effect of anticholinergic agents and potassium channel openers on urinary bladder response to pelvic nerve stimulation in anaesthetized dogs

1 Effects of the anticholinergic agents atropine, oxybutynin and terodiline, and the potassium channel openers YM934 (2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl) pyridine N-oxide) and cromakalim were examined on urinary bladder response to pelvic nerve stimulation in pentobarbital-anaesthetized dogs. 2 Pelvic nerve stimulation (PNS) produced a frequency-dependent increase in intravesical pressure in anaesthetized dogs. The response to PNS was abolished by topical tetrodotoxin, and markedly inhibited by intravenous hexamethonium, suggesting a neurogenic origin for the in vivo contractile response. 3 Atropine (0.3–3 mg kg^?1 i.v.) and the anti-neurogenic bladder agents, oxybutynin (1–10 mg kg^?1 i.v.) and terodiline (1–10 mg kg^?1 i.v.) dose-dependently decreased the amplitude of the peak intravesical pressure response to PNS. At either frequency of PNS, these agents inhibited the response to a similar degree. 4 The potassium channel openers YM934 (1–10 μg kg^?1 i.v.) and cromakalim (3–30 μg kg^?1 i.v.) dose-dependently decreased the amplitude of the peak intravesical pressure response to PNS. The inhibitory effects of these drugs were more potent at lower than at higher frequencies of PNS. 5 These data suggest that the inhibitory effects of potassium channel openers on urinary bladder response to PNS are different from those of anticholinergic agents. The preferential inhibitory effect of potassium channel openers on detrusor smooth muscle contraction at lower frequencies of PNS may represent new potential for the treatment of neurogenic bladder.     

骨盆骨折合并后尿道损伤继发性功能障碍临床诊断及治疗随访

目的回顾性分析骨盆骨折合并后尿道损伤继发性功能障碍的致病原因,并总结治疗经验。方法对2010年1月~2016年1月梅州市大埔县人民医院收治的60例骨盆骨折患者的病历档案进行调阅,通过不同的骨折程度将60例患者分为A组(稳定骨折,移位轻微),患者行尿道会师牵引固定术;B组(旋转不稳定、垂直稳定骨折,累及前后环),患者行尿道端端吻合术;C组(旋转及垂直均不稳定,稳直剪力),患者行盆骨复位内固定术。通过国际勃起功能指数和夜间阴茎胀大试验对患者阴茎勃起情况进行评价。结果 A、B、C三组损伤前和损伤后的IIEF评分以及手术治疗后和治疗6个月后的IIEF评分存在统计学意义(P<0.05)。A、B、C三组NPT结果显示三组的强度、时间、次数,三组比较差异有统计学意义(P<0.05)。在对三组术后3、6、12个月的性功能状态及生育情况进行随访,均具有统计学意义。结论盆骨骨折合并后尿道损伤继发性功能障碍与骨折的类型及部位有关。     

电针治疗宫颈癌根治术后膀胱功能障碍的机制研究

目的探讨电针治疗子宫颈癌术后膀胱功能障碍的临床效果和可能机制。方法回顾性分析两家医院2009年1月至2012年12月子宫颈癌术后患者120例,其中电针治疗组56例、常规治疗组64例,观察术后2周自主排尿成功率、术后2周尿动力学检测指标和术后膀胱功能障碍类别。结果电针治疗组和常规治疗组术后2周自主排尿成功率分别为83．93％（47／56）和70．97％（44／62）,两者比较无统计学差异（P=0．057）。电针治疗组术后2周膀胱顺应性高于常规治疗组,有统计学差异（P=0．046）,两组术后2周膀胱初感容积、最大膀胱容量、最大尿流率、最大尿流率时逼尿肌压力均无统计学差异（P〉0．05）。电针治疗组术后2周低顺应性膀胱和逼尿肌收缩力受损发生率均低于常规治疗组,有统计学差异（P=0．049,0．038）,两组术后2周逼尿肌过度活动、膀胱流出道梗阻和逼尿肌外括约肌协同失调发生率均无统计学差异（P〉0．05）。结论电针可以降低子宫颈癌术后2周膀胱功能障碍的发生风险,机制可能为提高膀胱顺应性和减轻逼尿肌收缩力受损。