Effects of selective autonomic and pudendal denervation on the urethral function and development of retention in female dogs

PURPOSE: This trial is an experimental approach to the possible causes of continence and voiding problems after urethra sparing radical cystectomy and orthotopic bladder substitution in women. MATERIALS AND METHODS: Between January 1996 and January 1999 we included 24 mongrel female dogs in this 4-phase study of 6 dogs each. The effects of autonomic denervation of the urethra (phase 1) and urethral transection just distal to the bladder neck (phase 2) on the urethral pressure profile were recorded. In phase 3 the effects of autonomic denervation, urethral transection and pharmacological manipulation of the denervated transected urethra on the urethral pressure profile were studied in succession. In phase 4 the effects of pudendal nerve transection and pharmacological blockade were recorded. In the 12 phases 2 and 3 dogs the transected urethra was re-anastomosed to the bladder neck. Acute experiments were repeated after 2 and 6 months, urethrocystoscopy was done and post-void residual urine was estimated. Two of the latter dogs were sacrificed 6 months after the acute experiment and the urethras were histopathologically examined. RESULTS: Autonomic denervation resulted in a 46% to 48% decrease in mean maximal pressure in the proximal urethra in phases 1 and 3 (p <0.001) with no significant effect on the distal urethra. Urethral transection in phase 2 did not affect the urethral pressure profile. Phentolamine injection after urethral denervation and transection in phase 3 produced a further reduction of 11.3% and 46.3% in mean resting pressure in the proximal and distal urethra, respectively, while succinyl choline produced a 38.1% further decrease in the distal urethra. Unilateral and bilateral pudendal denervation reduced pressure in the distal urethra significantly but not in the proximal urethra. When phentolamine was given thereafter, a further decrease of 38% and 2.4% resulted in resting pressure values in the proximal and distal urethra, respectively. The change in distal urethral pressure was marginally significant after succinyl choline injection (p = 0.05). Results were reproducible after 2 and 6 months. The proximal urethra remained patent with no post-void residual urine after autonomic denervation. There was no significant urethral fibrosis after realignment of the transected urethra in the 2 sacrificed phases 2 and 3 dogs. CONCLUSIONS: From this study we concluded that autonomic denervation reduced pressure in the proximal urethra by less than 50%. Continuity of the urethra with the bladder is not necessary for proper urethral function. After autonomic denervation the proximal urethra remained patent with no subsequent fibrosis. In addition, no post-void residual urine was noted. Bilateral pudendal denervation did not completely block activity of the distal urethra. The nonneuromuscular components had a small role in the creation of urethral closure function.     

Urodynamic evaluation of a bladder flap tube as urinary sphincter

The sphincteric properties of the normal urethra of seven female dogs were compared to those of a bladder flap tube pulled through the rectus muscle and anastomosed to the skin for urethral replacement. The functional length and distribution of closure pressure at rest were similar in the urethra and the bladder flap tube. When sneezing was triggered in the dogs to provoke a stress condition, contraction of the rectus muscle induced pressure changes in the distal neourethra similar to those obtained under the same stress condition from the striated urethral sphincter. However, with a full bladder, stress forced the newly fashioned bladder neck to open; yet, owing to sufficient resistance in the distal neourethra (rectus muscle), stress incontinence occurred only in two animals.     

Urethral function after cystectomy: a canine in vivo experiment

Summary To study the function of the pelvic floor and the isolated urethra after removal of the bladder, 5 male and 5 female mongrel dogs were used in an acute in vivo experiment. Urethral pressure changes secondary to unilateral stimulation of the pelvic and pudendal nerves were recorded. After baseline data of the intact system were documented, the following procedures were carried out: separation of the urethra from the bladder neck (prostate), nerve-sparing cystectomy (cystoprostatectomy), and cold-knife incision through the entire length of the proximal urethra. Pressure recordings were repeated after each step of surgery. Pudendal nerve stimulation resulted in rapid and large pressure rises in the distal urethra (reaction typical of striated muscle). This response remained unchanged after all three surgical steps. Pelvic nerve stimulation provoked pressure rises within the urethra of a pattern typical of smooth muscle. The findings persisted after separation of the urethra from the bladder neck (prostate) and after cystectomy, but were not observed after urethrotomy. Contractions secondary to pudendal nerve stimulation were inhibited by curare, which did not affect the reaction to pelvic nerve stimulation. Our experiments demonstrate that in the dog the continuity of bladder and urethra is not required for the function of urethral closure mechanisms. The contractile potency of the urethral smooth muscles remains intact after nerve-sparing cystectomy. We believe that problems with the baseline continence of surrogate bladders should mainly be ascribed to a lack of surgical caution in preserving the autonomic nerves of cystectomy. A poor response to stress conditions cannot be explained by damage to the neural pathway of the striated sphincter, as the pudendal nerve is not at risk during nerve-sparing cystectomy. In our opinion mechanical malfunction of the striated muscle components secondary to scarring at the site of the anastomosis is the main reason for stress incontinence after orthotopic bladder replacement.     

Differential expression of bladder neurotrophic factor mRNA in male and female rats after bladder outflow obstruction

PURPOSE: We validated a male rat model of bladder outflow obstruction and compared the expression of bladder neurotrophic factor mRNA in male and female rats 6 weeks after bladder outlet obstruction. MATERIALS AND METHODS: We examined the proximal urethra in male Wistar rats. Urethral lumen reducing ligatures were placed in 15 females and 19 males, while 10 male and 10 female controls underwent sham surgery. Awake cystometry was performed 6 weeks after surgery. Ribonuclease protection assay was used to measure changes in bladder neurotrophic factor mRNA expression in the 2 sexes. RESULTS: Average bladder capacity in rats with bladder outlet obstruction increased 3-fold in males and 4.4-fold in females compared with controls, while bladder weight increased 2.2 and 4.3-fold, respectively. Filling and threshold pressure increased significantly and nonvoiding bladder contractions were recorded in 100% of female and 80% of male rats with bladder outlet obstruction. An 8-fold increase in bladder brain derived neurotrophic factor mRNA was noted in each sex after obstruction. A 2-fold increase in bladder nerve growth factor mRNA after obstruction was only observed in females. CONCLUSIONS: This male rat model of bladder outlet obstruction was created by placing lumen reducing ligatures at the urethrovesical junction. The dramatic increase in bladder brain derived neurotrophic factor mRNA expression and differential expression of nerve growth factor mRNA in male and female rats with bladder outlet obstruction suggest that additional neurotrophic factors may contribute to the lower urinary tract neuroplasticity associated with bladder outlet obstruction and this contribution may be gender dependent.     

Role of the pelvic nerve in the dynamics of micturition in the decerebrate dog as determined by suprapubic endoscopical and urodynamic evaluation

The role of the pelvic nerves on the dynamics of micturition was evaluated in 13 decerebrate dogs, four male and nine female, by direct observation of bladder movement, by suprapubic cystoscopic observation of urethral behavior, and by pressure flow EMG studies. Experiments were performed before and after unilateral pelvic nerve transection. In control conditions and after unilateral pelvic nerve transection, the bladder neck was not tightly closed during the collecting phase, the membranous portion of the urethra opened and closed spasmodically during the emptying phase, and reflex micturition developed. Direct observation showed that after unilateral pelvic nerve transection, the ipsilateral bladder did not contract. A pressure flow EMG study showed that unilateral pelvic nerve transection produced a significant increase in threshold volume, threshold pressure, bladder compliance and residual volume, and a significant decrease in contraction pressure and flow rate. The present study shows that unilateral pelvic nerve transection has no demonstrable effect on urethral function, but has effects on bladder function during the collecting and emptying phases and that bladder innervation is unilateral in the dog.     

Urethral sensitivity and the impact on urinary continence in patients with an ileal bladder substitute after cystectomy

PURPOSE: After cystectomy and ileal bladder substitution, sensitivity in the membranous urethra correlates with postoperative urinary continence. We determine whether sensitivity is decreased only in the most proximal part of the urethra or also more distally in the bulbar urethra, which would give some indication as to which nerves may be injured during radical cystoprostatectomy. MATERIALS AND METHODS: The sensory threshold for electrical stimulation was measured with double ring electrodes in the membranous urethra, and 2.5 cm. distally to it in 41 men after cystectomy and ileal bladder substitution, and in a control group of 29 men. RESULTS: The mean sensory threshold plus or minus standard deviation of the membranous urethra was 9 +/- 2 mA. in the control group compared to 26 +/- 11 mA. in the postoperative group (p <0.001). Mean sensory threshold 2.5 cm. distal to the membranous urethra was 8 +/- 3 versus 9 +/- 3 mA. in the control and postoperative groups, respectively (not significant). Patients with daytime continence had a mean threshold of 22 +/- 8 mA. in the membranous urethra compared to 38 +/- 11 mA. in those who were incontinent (p <0.004) and a threshold of 8 +/- 3 mA. 2.5 cm. distal to the membranous urethra compared to 8 +/- 2 mA. in those who were incontinent (not significant). CONCLUSIONS: After cystectomy and ileal bladder substitution, urethral sensitivity 2.5 cm. distal to the membranous urethra is unaffected by surgery and does not correlate with postoperative continence. In contrast, a decreased sensitivity in the membranous urethra correlates with an increased risk of postoperative incontinence. Preservation of sensitivity in the membranous urethra seems to be an important factor for achieving continence after cystectomy and ileal bladder substitution, and does not seem to be dependent on the extrapelvic portion of the pudendal nerve.     

The urodynamic effects of an alpha 1-adrenoceptor agonist on the bladder and urethra of female dogs]

It has been known that alpha 1-adrenoceptors play an important role in urethral contraction. The incompetence of the urethral contraction is a cause of stress incontinence. We studied the urodynamic effects of a selective alpha 1-adrenoceptor agonist (midodrine hydrochloride) on the bladder and urethra of female dogs. Under anesthesia with intravenous chloralose, four doses (0.03, 0.1, 0.3 and 1.0 mg/kg) of midodrine were administered intravenously and urodynamic studies including cystometry, urethral pressure profilometry and electromyography (EMG) of the external urethral sphincter were performed. The administration of midodrine induced a significant increase of the maximum closing pressure in the proximal portion of the urethra (p less than 0.05 at 0.03 mg/kg and p less than 0.01 at 0.1, 0.3, 1.0 mg/kg). There were no significant changes in the functional profile length, the closing pressure at the external sphincters, the maximum bladder pressure, bladder capacity and bladder compliance. The administration of 0.3 mg/kg or more of midodrine produced a significant increase in the mean arterial blood pressure. After midodrine administration, transient increases in the external sphincter EMG activities were recognized. The activities showed the synergistic pattern during the bladder contractions. In conclusion, lower dose administration of a selective alpha 1-adrenoceptor agonist (midodrine) specifically produced an increase of the closing pressure in the proximal portion of the urethra without affecting blood pressure. These results suggest that midodrine is useful for the treatment of stress incontinence in humans.     

人工反射弧重建膀胱功能动物模型的建立

目的 :建立犬“膝腱 脊髓 膀胱”反射弧重建膀胱功能的动物模型 ,作为实验研究人工膀胱反射弧的基础。方法 :家犬 5条 ,行硬膜外L5 S2前根交叉吻接 ,饲养 1年后刺激反射弧并记录膀胱压和尿道压变化。结果 :5只家犬“膝腱 脊髓 膀胱”反射弧均成功建立 ,刺激反射弧时膀胱压和尿道压都有升高。结论 :通过硬膜外L5 S2前根交叉吻接可以更有效地建立人工反射弧重建膀胱功能的动物实验模型。     

Experimental studies on sympathetic innervation of lower urinary tract. Quantitation of nerve terminals and urethral pressure response after hypogastric denervation

On 6 female mongrel dogs (denervated group), bilateral hypogastric nerves were cut distally to the inferior mesenteric ganglion. Five dogs were kept intact as a control group. After 2-5 months, urethral pressure response to continuous noradrenaline infusion (0.1 microgram/kg/min) was monitored. The urethral pressure rose significantly after noradrenaline loading in each group, however there was no significant difference in the degree of the response between the denervated group and control group. Subsequently, the bladder and the urethra were extirpated to determine the intrinsic noradrenaline content. The tissue noradrenaline concentration was highest in the posterior urethra, intermediate in the bladder base and lowest in the bladder dome. Although these values tended to be lower in the denervated group than in the control group, no significant difference was obtained between the groups in each portion. These results suggest that the majority of sympathetic components which consists in the hypogastric nerve may involve short adrenergic neurons. Thus, chronic hypogastric denervation alone does not induce sympathetic denervation supersensitivity. Simultaneous decentralization of the pelvic nerve may be necessary for inducing sympathetic denervation supersensitivity.     

腰骶神经吻合对自主性神经原性膀胱排尿功能影响的实验研究

目的:探讨通过腰骶神经吻合恢复或改善神经原性膀胱排尿功能的可行性.方法:10只家犬手术前先行尿流动力(包括膀胱容量、压力、顺应性)及肛门括约肌肌电图(EMG)测定,作为对照组数据.检测完后处死2只.取其S1、S2神经根,共8根作为对照组,行HE染色观察有髓和无髓神经纤维数量.其余8只犬为实验组,将L4与S1、L5与S2神经根分别端端吻合.术后4个月行尿流动力学测定,术后7个月再次行尿流动力学测定后处死动物,取L4、L5和S1、S2神经根吻合口段和骶神经干段行HE染色,观察有髓和无髓神经纤维数量.结果:术后4个月,实验组犬膀胱容量、顺应性和对照组比较明显增加(P<0.05);膀胱压力、肛门括约肌EMG的电压明显降低(P<0.05).术后7个月,实验组犬膀胱压力和肛门括约肌EMG的电压和对照组比较无明显降低(P>0.05);而膀胱容量和顺应性明显增加(P相似文献   

骶神经根选择性切断治疗截瘫后痉挛性膀胱的实验及临床研究

目的观察高选择性骶神经根前根切断术治疗脊髓损伤后痉挛性膀胱的疗效,探讨其治疗机制、最佳手术方法及临床实际疗效. 方法雄性家犬12只,制成脊髓损伤后痉挛性膀胱模型,根据骶神经根切断方式:切断S2前根,切断S2前根 S3 1/2前根,切断S2、S3前根,完全切断S2～4神经根,依序分为A、B、C、D 4个组,通过尿动力学检测及电生理观察,分析比较骶神经根切断前、后各组功能性指标的变化,确定其最佳手术方案.临床治疗则根据实验结果,选择性切断脊髓损伤后痉挛性膀胱患者S2前根或 S3 1/2前根共32例.术前膀胱容量平均(120±30) ml,术前排尿量平均(100±30) ml,尿道压力平均为(120±20) cm H2O. 结果 4个组术后膀胱容量分别为:(150±50)、(180±50)、(230±50)、(400±50) ml;排尿量分别为:(130±30)、(180±50)、(100±50)、(50±30) ml.临床治疗32例,术后膀胱容量平均增加至410 ml左右,排尿量平均增加至350 ml左右,所有患者尿失禁消失.有13例获22个月远期随访,无复发. 结论高选择性骶神经根切断治疗脊髓损伤后痉挛性膀胱疗效显著,是一种值得研究、推广的新方法.     

Urethral response to nerve stimulation measured by strain gauge force transducer

This paper presents a study of urethral responses to efferent nerve stimulation in dogs. The pelvic, hypogastric and pudendal nerves were stimulated using a programmed instrument under three different in vivo conditions. The preparations consisted of: (A) bladder, urethra, and rectum; (B) urethra and rectum, and (C) urethra only. Stimulation of the pelvic nerve in preparation A resulted in elongation and constriction of the mid and proximal urethra with a resultant rise in pressure. However, this response was reduced in preparations B and C. Similar observations were made with hypogastric nerve stimulation. The results of pudendal nerve stimulation were significantly different, in that the pressure rise occurred in the mild and distal urethra and varied in elongation response.     

女性控尿机制的研究及其在原位新膀胱术中的应用

近10多年来,随着对女性人体盆腔和尿道局部解剖学的深入研究,临床泌尿外科医师对膀胱颈、尿道、横纹括约肌、尿道支持组织及这些结构的神经支配在女性控尿中的作用有了新的认识,指导和推动了原位新膀胱术在女性患者中的应用,提高了临床效果和患者生活质量。本文就有关女性控尿机制及其在原位新膀胱术中的应用进展作一介绍。     

A magnetic device for increasing the urethral resistance to flow: an experimental study in female dogs

OBJECTIVE: To test a new magnetic device for increasing the urethral resistance to flow in a dog model, and thus provide a potential mechanical device for the treatment of incontinence in women. MATERIALS AND METHODS: The study comprised 12 female mongrel dogs; three dogs were used to study the effect on urethral resistance of inserting a vaginal magnet (control experiment) and five were assessed in a urodynamic study. With the animals under general anaesthesia, the bladder and the urethra were exposed by a low midline incision. One magnet, embedded in a silicon layer, was placed on the anterior side of the urethra 3 cm distal to the bladder neck and fixed with a few sutures. To increase the urethral resistance as required, a second magnet was inserted into the vagina and the device activated. Urethral pressure profiles and leak-point pressures were recorded in the anaesthetized animals under resting conditions and after the urethra was compressed between the magnets. Recordings were also made after pharmacological blockade of the urethral musculature. In four additional dogs, chronic experiments were conducted to evaluate the effect of continuous compression of the urethra and the vaginal wall for 14 days. RESULTS: Urethral compression between the magnets resulted in a doubling of the maximal pressure in the proximal urethra and in a threefold increase of the leak-point pressure. After pharmacological denervation of the urethra the differences between the control pressures and those after activating the device were even greater, although not significantly so. After 2 weeks of continuous compression of the vaginal wall and the urethra between the magnets there was no detectable tissue damage. CONCLUSION: These results suggest that the magnetic device can efficiently increase urethral pressure and that prolonged compression caused no apparent damage to the urethra or vagina. It may therefore be a useful potential method of providing urinary continence in women.     

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.     

A study of the myelinated fibres in the branches of the pelvic plexus

In a 20-year-old human female specimen the nerves to the pelvic organs were dissected and analysed. The gross anatomy of the branches of the pelvic plexus was described. The composition of these nerves was studied and the sizes and distribution of the diameter of a great part of the myelinated nerve fibres were measured and analysed. It was confirmed that the ventral roots S2 and S3 contain many nonmyelinated nerve fibres. There are direct connections between the sacral sympathetic chain and the pelvic plexus. They contain myelinated fibres with sizes as large as 11 μm. There are two different groups of fibres which supply the bladder, one on the dorsal side, mainly nonmyelinated (postganglic sympathetic?), and another group to the lateral side which contains many thin myelinated fibres (parasympathetic preganglionic?). The pelvic plexus and its branches are fixed to the vagina and the rectum. Surgical interventions in this area and perhaps also childbirth can damage the nerve supply to the bladder and the urethra. The functional disturbances of the bladder after such interventions can depend on what group of nerve fibres is most seriously damaged. The large number of thick myelinated fibres which reach the ventro lateral side of the urethra makes it highly probable that these fibres innervate the intrinsic striated urethral musculature. The large number of nonmyelinated nerve fibres in the nerves to the m. levator ani probably innervate smooth muscle tissue which is found in the fasciae of the pelvic floor.     

The structure and innervation of smooth muscle in the wall of the bladder neck and proximal urethra.

Neurohistochemical and electron microscopic techniques have been employed to compare the structure and autonomic innervation of the bladder detrusor with that of the bladder neck and urethra in male and female cats, rats and guinea-pigs. In all specimens the structure and arrangement of smooth muscle in the detrusor was different from that in the bladder neck and proximal urethra. In male specimens this circular smooth muscle extended into the proximal urethra as far as the entrance of the ejaculatory ducts. A similar muscle coat was less well developed in the female but could be identified along the length of the urethra. Differences in the distribution of autonomic nerves have also been demonstrated. Presumptive cholinergic nerves were frequently encountered amongst the smooth muscle cells of the detrusor whilst noradrenergic nerves were relatively sparse. In contrast, muscle in the bladder neck and urethra was richly innervated by both types of autonomic nerve. In the male these findings are considered to provide support for the concept of a sphincteric mechanism which prevents retrograde ejaculation. In both sexes the possible functional role of the autonomic innervation of the bladder neck and proximal urethra during micturition has also been discussed.     

Selective activation of the sacral anterior roots for induction of bladder voiding

AIM: We investigated the efficacy of selective activation of the smaller diameter axons in the sacral anterior roots for electrically induced bladder voiding. MATERIALS AND METHODS: Acute experiments were conducted in five adult dogs. The anterior sacral roots S2 and S3 were implanted bilaterally with tripolar electrodes. Pressures were recorded from the bladder and from the proximal urethra and the external urethral sphincter. A detector and flow meter monitored fluid flow. A complete sacral dorsal rhizotomy was carried out. The effects of two types of pulse trains at 20 Hz were compared; quasitrapezoidal pulses (500 microsec with 500 microsec exponential decay) and interrupted rectangular (100 microsec, 2 sec on/2 sec off). Before rhizotomy, rectangular pulse trains (100 microsec) to activate all fibers were also applied. The experimental design was block randomized before and after rhizotomy. RESULTS: Quasitrapezoidal pulses showed block of sphincter activation with average minimum current for maximum suppression of 1.37 mA. All pulse types evoked average bladder pressures above the basal sphincter closure pressure. The pressure patterns in the proximal urethra closely followed the bladder pressures. Before dorsal rhizotomy, stimulation evoked a superadded increase in sphincter pressures with slow rise time. After rhizotomy, the sphincter pressure patterns followed the bladder pressures during selective activation and voiding occurred during stimulation with quasitrapezoidal trains and in between bursts with interrupted rectangular stimulation. CONCLUSIONS: Selective activation of sacral ventral roots combined with dorsal rhizotomy may provide a viable means of low-pressure continuous voiding in neurological impairment.     

Role of the pudendal nerves on the dynamics of micturition in the dog evaluated by pressure flow EMG and pressure flow plot studies

The role of the pudendal nerves on the dynamics of micturition was studied using 16 decerebrated dogs. The voiding cycles were analyzed by pressure flow EMG and pressure flow plot studies under 3 conditions: control, after unilateral, and after bilateral pudendal nerve transection. In the control condition, highly reproducible reflex micturition with bladder contraction and spasmodic rhythmic sphincter contractions was demonstrated. Two patterns were noted following pudendal nerve transection: reflex micturition and overflow incontinence. Even though reflex micturition could be achieved in 9 out of 16 dogs after bilateral transection, there was decreased bladder emptying as well as absence of spasmodic rhythmic sphincter contractions. Overflow incontinence developed in the remaining 7 dogs (5 dogs after bilateral transection and 2 dogs after unilateral transection). It appears that the pudendal nerves play an important role in emptying the bladder of the dog.     

Urodynamic Analysis of Age-Related Changes of alpha sub 1 -Adrenoceptor Responsiveness in Female Beagle Dogs

Purpose

We have evaluated age-related changes of alpha₁-adrenoceptor responsiveness in the lower urinary tract of female beagle dogs by urodynamic analyses.

Materials and Methods

Six aged parous and 6 young nonparous female beagle dogs were studied. Mean ages (plus/minus standard error of the mean) of the 2 groups were 68.3 plus/minus 2.3 and 12.4 plus/minus 0.08 months. Before and after 4 administrations of alpha₁-adrenoceptor agonist (midodrine hydrochloride 0.03, 0.1, 0.3 and 1.0 mg./kg. intravenously), cystometry, urethral pressure profilometry and external urethral sphincter electromyography were performed.

Results

After 0.3 mg./kg. midodrine administration, mean bladder capacity in the aged dogs significantly decreased, compared with that in the young dogs (p less than 0.05). After the minimum dose administration (0.03 mg./kg.), the urethral closing pressure in both groups increased significantly (p less than 0.05) with no changes in bladder capacity or arterial blood pressure. The proximal urethral closing pressure in the aged dogs increased dose dependently. After administration of 1.0 mg./kg. drug it reached 257 percent of the initial values (p less than 0.01), which was significantly greater than that in the young dogs (p less than 0.05).

Conclusions

These findings suggest that 1) age-related increase of alpha₁-adrenoceptor responsiveness occurs in the bladder and in the proximal urethra. The former may be one of the etiologies of detrusor instability in the elderly. 2) A lower dose of midodrine hydrochloride may be useful for the treatment of stress incontinence, independent of age.