Multicenter, randomized, sham-controlled study on the efficacy of magnetic stimulation for women with urgency urinary incontinence.

OBJECTIVES: To evaluate the efficacy and safety of magnetic stimulation for the treatment of urinary incontinence in women with overactive bladder. METHODS: A total of 151 women with urgency incontinence were randomized to the active stimulation group or the sham stimulation group in a 2:1 order. An armchair type magnetic stimulator was used for 25-min magnetic stimulation twice a week, with the maximum magnetic flux density of 560 mT peak at 10 Hz. The sham device was set to deliver in a 5-s "on"-5-s "off" pulsing manner with the maximum intensity of 20.4% of active stimulation at 1 Hz. The study consisted of a baseline period for 1 week, and a treatment period for 6 weeks. The primary end-point was the number of leaks/week from the bladder diary. The secondary end-points were the number of voids and urgency/24 h, mean and maximum voided volume, and the quality of life assessment. RESULTS: Changes from baseline in the active and sham group, respectively, were -13.08 ± 11.00 and -8.68 ± 13.49 in leaks/week (P = 0.038), -2.65 ± 2.52 and -1.53 ± 2.39 in number of urgency/24 h (P = 0.011), and 14.03 ± 34.53 mL and -4.15 ± 40.60 mL in mean voided volume (P = 0.0056). As for safety, except for diarrhea and constipation, no patients experienced any device-related adverse event. CONCLUSIONS: Magnetic stimulation is effective for the treatment of urgency incontinence in female patients with overactive bladder.

Surgical treatment of urethral distraction defect associated with pelvic fracture: a nationwide survey in Japan.

OBJECTIVE: To survey practice patterns in surgical treatment for urethral distraction defect associated with pelvic fracture (PFUDD) and to analyze outcomes of the treatment in Japan. METHODS: A questionnaire on surgical treatment for PFUDD to 3307 Japanese consultant urologists was sent. Responses were collected and statistically analyzed. RESULTS: The number of respondents was 1290 (39%). Patients surgically treated for PFUDD in the previous 5 years totaled 0 for 919 urologists (71%), one to two for 283 (22%), and three to ten for 83 (7%) urologists. Realignment for PFUDD was carried out within 2 weeks in 205 patients (23%), after 2-6 months in 607 (69%) patients, and after more than 6 months in 72 (8%) patients. Urologists operated on 361 (61%) patients endoscopically (ES), 108 (18%) by open anastomosis (OA) and 101 (17%) by pull-through operation (PT). According to the operator's impression, success rates were 65% for ES, 79% for PT and 69% for OA. Re-operation (RO) rates were 43%, 25% and 26% for ES, PT, and OA, respectively, (ES vs PT or OA; P < 0.05). Postoperative repeated urethral dilatation (PORUD) was required in 71% of ES, 77% of PT and 38% of OA cases (OA vs ES or PT; P < 0.05). CONCLUSIONS: PFUDD represents a rare disorder for Japanese urologists. Deferred endoscopic realignment is the preferred treatment option. Success rates were not different among three surgical treatments. OA was superior to ES and PT in terms of PORUD and RO.

Variety of congenital urethral lesions in boys with lower urinary tract symptoms and the results of endoscopic treatment.

OBJECTIVES: We described various types of congenital urethral anomalies seen in boys with LUTS such as refractory enuresis. Their urethrograpic and endoscopic finding were reviewed and the effect of trans-urethral incision (TUI) was analyzed. PATIENTS AND METHODS: We evaluated 67 boys with lower urinary tract symptoms (LUTS, mean: 9 years old), in a period of three and a half years. A voiding cystourethrogram (VCUG) was performed in 37 patients and if we suspected a urethral abnormality, endoscopy was performed. Congenital urethral obstruction was diagnosed from VCUG and endoscopic findings and classified into Types 1, 3 and 4 posterior urethral valves (PUV) according to Douglas Stephens' description. Trans-urethral incision (TUI) was carried out for congenital urethral obstruction and the effect was judged three months later. RESULTS: On VCUG, 17 patients (45.8%) had an abnormal urethral configuration. On endoscopy, nine patients (24.3%) were diagnosed as having PUV. The effect of TUI on PUV excluding Type 3 was 80%, while that on Type 3 was 25%. DISCUSSIONS: The incidence of PUV compared to bulbar urethral narrowing was significantly different from that described in previous Japanese reports, but similar to other countries. The reason is thought to be the lack of standardized interpretations of VCUG images and endoscopic findings, resulting in the overestimation of the bulbar urethral lesion. CONCLUSION: The incidence of PUV in Japanese boys with LUTS was higher than had ever been described. The improvement rate by TUI was high in PUV excluding Type 3, but low in Type 3. The ring like strictures at the bulbar urethra may be less important than has previously been thought.

Randomized, double-blind, sham-controlled evaluation of the effect of functional continuous magnetic stimulation in patients with urgency incontinence.

AIMS: To evaluate the effect of functional continuous magnetic stimulation (FCMS) on urgency incontinence in randomized, sham-controlled manner. METHODS: Thirty-nine patients with urgency incontinence, 16 males and 23 females (aged 66.0 +/- 16.5 years), who were refractory to pelvic floor muscle training (PFMT), were randomly assigned either to the treatment schedule performing 10-week active treatment, followed by 4-week non-treatment interval and then by 10-week sham treatment (A-S, n = 20) or to that performing the sham treatment first followed by 10-week active treatment (S-A, n = 19). RESULTS: At 10 weeks, the number of leaks/week, the total score of the International Consultation on Incontinence-Questionnaire: Short Form (ICIQ-SF), and maximum cystometric capacity (MCC) were significantly improved as compared with the initial levels (P < 0.001, P < 0.001, and P = 0.003, respectively) in the former group, but not in the latter group. Four (20.0%) patients were cured in the A-S group, while no patient was cured in the S-A group. At the end of the A-S schedule (24 weeks of study), the effect of the active treatment was still maintained at a significantly improved level, as compared with the initial level. At the end of the S-A schedule, the number of leaks/week was significantly improved as compared with the initial level and with its 10-week level (P < 0.001 and P = 0.049, respectively), as well as ICIQ-SF total score (P = 0.001 and P = 0.006, respectively). MCC significantly increased from its initial level (P = 0.030). CONCLUSION: Magnetic stimulation was effective on urgency incontinence in comparison to sham stimulation in this small patient group.

Effects of 138-355, a beta3-adrenoceptor selective agonist, on relaxation of the human detrusor muscle in vitro.

AIMS: Beta-adrenoceptors are the predominant beta-adrenoceptor subtype present in the bladder and urethra. This study investigates the effects of 138-355, an active-metabolite of TT-138 and beta(3)-adrenoceptor agonist, on relaxation of the human detrusor in vitro. METHODS: Tumor-free tissue samples of human bladder muscle from 39 patients undergoing total cystectomy due to bladder cancer were obtained, and the mucosa and serosa were removed. Tissues were mounted in 5 or 10 ml organ baths containing Krebs solution, which was gassed with 95% O(2) and 5% CO(2). Resting tension of 1 g was obtained. When the contraction had stabilized, increasing concentrations of beta adrenoceptor agonists (non-selective, isoprenaline; beta(2)-selective, clenbuterol; beta(3)-selective, 138-355 and BRL37344) and propiverine (a non-selective anti-muscarinic antagonist) were added cumulatively and concentration-relaxation curves (CRCs) were obtained. CRCs to 138-355 were obtained in the absence and presence of SR59230A, a beta(3)-selective antagonist, and antagonist affinity values (pA(2)) were calculated from the Schild plot. RESULTS: Isoproterenol, clenbuterol, 138-355 and BRL37344 concentration-dependently relaxed isolated human urinary bladder strips with pEC(50) value being 6.76+/-0.17, 5.23+/-0.22, 5.80+/-0.26 and 5.90+/-0.28, respectively. Following antagonist assay, it was observed that concentration-relaxation curves to 138-355 was competitively antagonized by beta(3)- adrenoceptor antagonist, SR59230A, with a pA(2) value of 7.01+/-0.45 and with a Schild slope of 0.72+/-0.07. CONCLUSIONS: Involvement of the beta(3)-adrenoceptor appears to be greater than that of the beta(3)-adrenoceptor for relaxations of the human bladder. The relaxation response of 138-355 appears to be mediated via the beta(3)-adrenoceptor stimulation.

Incomplete emptying and urinary retention in multiple-system atrophy: when does it occur and how do we manage it?

Neurogenic urinary retention can be a major cause of morbidity in multiple-system atrophy (MSA). However, the timing of its appearance has not been entirely clear, and neither have the medical and surgical modalities for managing patients. We present the data obtained from our uroneurological assessment and therapeutic interventions at various stages of MSA. We recruited 245 patients with probable MSA. We measured postvoid residuals (PVR) and performed EMG cystometry in all patients. The grand average volume of PVR was 140 mL (range, 0-760) in our patients. The average PVR volume was 71 mL in the first year, increasing to 129 mL in the second year and 170 mL by the fifth year. The percentages of patients with complete urinary retention, acontractile detrusor, and detrusor-sphincter dyssynergia (DSD) also increased. The increase in PVR resulted in a decrease in functional bladder capacity, together with an increase in detrusor overactivity and neurogenic sphincter EMG. Clean intermittent self-catheterization (CISC) was introduced in most patients. Bladder-oriented therapy (cholinergic agents) had a limited value, whereas urethra-oriented therapy benefited patients with DSD (surgery) for up to 2 years, but syncope occurred in a subset of patients (alpha-blockers). MSA patients present with large PVR by the second year of illness, and that large PVR secondarily causes urinary frequency. CISC is the recommended treatment for most patients. Urethra-oriented medication and surgery benefit patients who would have difficulty performing CISC, although careful consideration of the short-term efficacy and potential adverse effects of these alternatives is mandatory.

Study on the relation of the shape of the uroflowmetrogram and the urethral loss coefficient calculated from the uroflowmetrogram.

The shape of the uroflowmetrogram reflects voiding conditions. Using a voiding simulation, we examined whether the urethral loss coefficient (LC) calculated from the approximated uroflowmetrogram correlates with parameters that regulate the shape of the uroflowmetrogram. A total of 161 normal and abnormal uroflowmetrograms were used. Normal female subjects and patients before and after transurethral resection of the prostate (TURP) were also studied. The ratio of maximum flow rate (Q(max)) to flow time (T), a parameter expressing the shape of the uroflowmetrogram, was calculated. The uroflowmetrograms were approximated using a voiding model, and the urethral LC was calculated. As a result, a strong negative correlation was observed between the Q(max)-flow time ratio, Q(max)/ T, and LC. Q(max)/T is the vertical to horizontal ratio of the uroflowmetrogram and indicates the average degree of acceleration of flow rate during voiding. On the other hand, urethral LC, which can be estimated from the shape of the uroflowmetrogram, is considered a kind of urethral resistance. We concluded that when urethral resistance is high, the degree of acceleration of flow rate is low on average. Our study also indicated that Qmax/T was less affected by voided volume (VV) compared to Q(max). As Q(max)/T is not as dependent on VV, it is useful for comparing cases with different VV.

Non-invasive estimation of intraurethral pressure profile from uroflowmetric curve.

BACKGROUND: An intraurethral pressure-time profile as urodynamic information was obtained in a non-invasive manner using an equivalent equation as a voiding model. METHODS: The reasonability of the voiding model was confirmed by applying it to an experimental flow curve likened to urinary flow. The flow curve was approximated and the pressure profile was estimated. From the uroflowmetric curves obtained in a normal subject and a patient with bladder outlet obstruction, the respective intraurethral pressure profiles were estimated. RESULTS: The pressure profile estimated from the approximated flow curve was found consistent with the profile of the difference between the pressure actually measured at two different portions in the experimental system. CONCLUSION: Non-invasive estimation of intraurethral pressure profile from uroflowmetric curves may be very useful to grasp intraurethral urodynamic information in clinical practice.

Single-blind, randomized controlled study of the clinical and urodynamic effects of an alpha-blocker (naftopidil) and phytotherapy (eviprostat) in the treatment of benign prostatic hyperplasia.

AIM: The aim of our study was to examine the efficacy of naftopidil in terms of the international prostate symptom score (IPSS) and urodynamic parameters in the treatment of benign prostatic hyperplasia (BPH). Eviprostat was used as a control to study the efficacy of naftopidil. METHODS: Forty-nine patients with BPH (mean age 67.9 +/- 7.8 years) were involved in the study. Patients were randomly assigned either to the naftopidil group, which was treated with the alpha-blocker naftopidil (50-75 mg daily, 36 patients), or the eviprostat group, which was treated with phytotherapy (six tablets of eviprostat daily, 13 patients). RESULTS: The mean total IPSS, the total storage and voiding symptom scores, and the quality of life score decreased significantly (P < 0.0001 for each variable) in the naftopidil group, but not in the eviprostat group. In the naftopidil group, analyses showed significant increases in average and maximum flow rate and bladder capacity at first desire to void (P < 0.001, P = 0.001 and P = 0.024, respectively), and significant decreases in the postvoid residual, the percent of residual and the Abrams-Griffiths number (P = 0.009, P = 0.008 and P = 0.042, respectively). However, in the eviprostat group, no significant changes were noted in terms of these symptomatic and urodynamic parameters. In the pressure/flow study, an improvement in the International Continence Society nomogram grade was noted in 29% of the naftopidil group, but in only 16% of the eviprostat group. Among the 14 patients in the naftopidil group, detrusor overactivity disappeared in 21% and cystometric capacity increased in 36%, but no improvement in detrusor overactivity was noted in the eviprostat group. CONCLUSIONS: Naftopidil appears to have been effective in this short-term treatment of BPH.

A pilot study evaluating a new questionnaire for prostatic symptom scoring, the SPSS, and its sensitivity as constructed to objective measures of outflow obstruction.

AIM: To evaluate the extent to which our newly developed questionnaire, the Saitama Prostate Symptom Score (SPSS), for prostatic symptom scoring reflects objective findings in benign prostatic hyperplasia (clinical BPH) and to compare it with the International Prostate Symptom Score (IPSS) with regard to diagnostic sensitivity in clinical BPH. METHODS: In this study, both the SPSS and the IPSS were self-administered by patients. Free uroflowmetry, a pressure-flow study and the measurement of prostatic volume were carried out. RESULTS: There was no significant correlation between the results of the IPSS questionnaire and the urethral obstruction grade estimated by Schaefer or Abrams-Griffiths nomograms. The total score of the SPSS was correlated with these nomograms (P = 0.0487 and P = 0.0413, respectively). There was no significant correlation between the results of the IPSS questionnaire and the total volume or transition zone volume of the prostate, whereas the total score of the SPSS correlated with the total volume of the gland and transition zone volume (P = 0.0044 and P= 0.0051, respectively). CONCLUSION: This study revealed the SPSS to correlate with objective findings satisfactorily. However, there are still several aspects of the SPSS which need to be improved upon, and the questionnaire should be studied in larger numbers of patients suffering from lower urinary tract symptoms.

Combination of a cholinergic drug and an alpha-blocker is more effective than monotherapy for the treatment of voiding difficulty in patients with underactive detrusor.

AIM: The aim of the present study was to compare the effectiveness of a cholinergic drug, an alpha-blocker and combinations of the two for the treatment of underactive detrusor. METHODS: One hundred and nineteen patients with underactive bladder were assigned to three groups: the cholinergic group, consisting of 40 patients taking bethanechol chloride (60 mg/day) or distigmine bromide (15 mg/day); the alpha-blocker group, consisting of 38 patients taking urapidil (60 mg/day); and the combination group, consisting of 41 patients taking both a cholinergic drug and an alpha-blocker. The effectiveness of each therapy was assessed 4 weeks after initialization of the therapy. RESULTS: Total urinary symptom scores (International Prostate Symptom Score, IPSS) remained unchanged after the cholinergic therapy, but were significantly lower after the alpha-blocker treatment (P = 0.0001) and the combination therapy (P = 0.0001). With regard to the total IPSS, there were significant differences between the cholinergic and the alpha-blocker groups (P = 0.0008), and also between the cholinergic and combination groups (P = 0.0033), in favor of the latter. The average and maximum flow rates did not increase significantly after monotherapy with either the cholinergic drug or the alpha-blocker, but they significantly increased after combination therapy compared to baseline values (P = 0.0033 and P= 0.0004, respectively). Postvoid residual volume did not decrease significantly after the cholinergic drug therapy, but decreased significantly after the alpha-blocker (P = 0.0043) and the combination therapies (P = 0.0008). The percentage of residual urine decreased significantly after therapy in all groups (P = 0.0005, P= 0.0176 and P= 0.0001, respectively). CONCLUSION: Combination therapy with a cholinergic drug and an alpha-blocker appears to be more useful than monotherapy for the treatment of underactive detrusor.

The functional role of beta-adrenoceptor subtypes in mediating relaxation of pig urethral smooth muscle.

PURPOSE: The predominant beta-adrenoceptor subtype present in the bladder and urethra is beta3-adrenoceptors. We investigated the role of beta-adrenoceptors in mediating relaxation of the in vitro female pig urethra. MATERIALS AND METHODS: Circular strips of urethral tissues were pre-contracted with KCl. Concentration-relaxation curves (CRCs) to beta-adrenoceptor agonists were obtained in the absence and presence of antagonists. RESULTS: The nonselective beta-agonist isoproterenol in 30 animals and the beta3-adrenoceptor agonist BRL37344 in 4 relaxed with high potency (pEC50 7.2 and 8.1, respectively), while the beta2-adrenoceptor agonist salbutamol in 6 had low potency (pEC50 6.1). Mean maximal relaxation responses of BRL37344 and salbutamol relative to maximal isoproterenol responses were 89.8% and 76.7%, respectively. Propranolol (10 to 100 nM) in 18 animals antagonized CRCs to isoproterenol with high affinity (apparent pKB 8.6) but the Schild plot had a slope that was significantly less than unity (0.68, p <0.01). High concentrations of the beta1-antagonist CGP20712A (3 to 30 microM) in 12 animals had no effect on responses to isoproterenol. The beta2-antagonist ICI118551 (30 to 300 nM) in 25 animals antagonized responses to isoproterenol with high affinity (apparent pKB 8.03) with a Schild slope not different from unity (0.79). The beta3-antagonist SR59230A (10 to 100 nM) in 12 animals antagonized CRCs to isoproterenol with an apparent pKB of 7 and with a Schild slope that was again significantly less than unity (0.62, p <0.01), indicating that responses to isoproterenol are mediated by more than 1 beta-adrenoceptor subtype. According to the Schild plot of unity ICI118551 (3 to 30 nM) in 18 animals competitively antagonized responses to salbutamol with high affinity (pA2 8.5). CONCLUSIONS: In the pig urethra beta-adrenoceptor mediated relaxations to isoproterenol are mediated via beta2 and beta3-adrenoceptors, while responses to beta2-adrenoceptor agonists such as salbutamol appear to be mediated only via beta2-adrenoceptors.

Urodynamic evaluation of surgical outcome in patients with urinary retention due to central lumbar disc prolapse.

AIMS: To investigate whether acute urinary retention due to central lumbar disc prolapse is reversible after emergency spinal surgery. METHODS: Eight patients (two males, six females) with a mean age of 31.5 years (range, 18-42 years) with urinary retention due to lumbar disc prolapse were studied. An emergency surgery was performed within 48 hours (mean, 42 hours) after the onset of urinary retention. Urodynamic study was performed before and after the operation. RESULTS: All patients had acontractile detrusor without bladder sensation and four of seven patients had inactive external sphincter on electromyogram at presentation. Two patients were unable to void up to 1 and 5 months after surgery and were then lost for follow-up. The remaining six patients could void with straining or changing their voiding postures (bending forward), postoperatively. A follow-up urodynamic study was performed in all patients from 1 month to 6 years postoperatively. All patients demonstrated acontractile detrusor on cystometrogram. On external sphincter electromyogram, four patients had normal activities. The remaining four patients recovered electromyographic activities, but two of them had denervation motor unit potentials and two had low activities. CONCLUSIONS: Bladder function was irreversible after spinal surgery, whereas urethral function showed a better recovery in patients with acute urinary retention due to central lumbar disc prolapse. However, most of our patients could empty their bladder only by straining or changing their voiding postures postoperatively.

Changing concepts in urological management of the congenital anomalies of kidney and urinary tract, CAKUT.

Recent advancement in ultrasonographic evaluation has prompted early detection and diagnosis of congenital anomalies in the kidney and urinary tract (CAKUT) in the asymptomatic phase. Consequently, early surgical intervention has become possible in the asymptomatic phase for the purpose of controlling manifestations early, thereby avoiding renal functional deterioration. However, some lesions detected by ultrasonography have been shown to often resolve or disappear without intervention. Thus, it has become more important to identify and understand the natural history of CAKUT. For the precise evaluation of the results of surgical intervention, one must understand the maturational process of renal function during infancy. Without considering this process, we cannot differentiate the renal significance of the surgical management from the natural course of CAKUT. Recent advancement in the field of radioisotopic studies has also made a major contribution to the more precise assessment of renal function. Recent progress in the understanding of the pathophysiology and the natural history of CAKUT has helped rationalize its treatment and management. Improvement in the surgical techniques and tools, together with improvements in pediatric anesthesiology, have made an appreciably positive impact on the outcome. Herein, we present the emerging concepts in the urological management of CAKUT, specifically, multicystic dysplastic kidney, vesicoureteral reflux, congenital hydronephrosis, ectopic ureters and ureteroceles.

Role of beta-adrenoceptor subtypes in mediating relaxation of the pig bladder trigonal muscle in vitro.

AIMS: To investigate the role of beta-adrenoceptor subtypes in mediating relaxation of the pig bladder trigonal muscle in vitro. MATERIALS AND METHODS: Longitudinal strips of trigonal muscle were isolated, and the mucosa and serosa removed. Tissues were precontracted with KCl, and beta-adrenoceptor agonists (isoprenaline or salbutamol) were added cumulatively, and concentration-relaxation curves (CRCs) were obtained. CRCs to agonists were obtained in the absence and presence of antagonists and antagonist affinity values were calculated. RESULTS: Isoprenaline (non-selective beta-agonist) relaxed with high potency (pEC(50) = 7.2). Propranolol antagonized CRCs to isoprenaline with a high affinity (apparent pK(B) = 8.8), but the Schild plot had a slope significantly (P < 0.01) less than unity (0.61), suggesting that responses were mediated by more than one beta-adrenoceptor subtype. CGP20712A (beta(1)-antagonist) antagonized responses to isoprenaline with a low affinity (apparent pK(B) = 5.13), indicating beta(1)-adrenoceptors did not participate in the response. The affinity of ICI118551 (beta(2)-antagonist) for antagonism of responses to isoprenaline was also relatively low (apparent pK(B) = 6.9), and the Schild slopes were significantly (P < 0.01) less than unity (0.58). SR59230A (beta(3)-antagonist) antagonized CRCs to isoprenaline with a relatively low affinity (apparent pK(B) = 7.5), and with a Schild slope significantly (P < 0.01) less than unity (0.86), indicating that responses may be mediated by more than one beta-adrenoceptor subtype. In contrast to that observed with isoprenaline, the beta(2)-adrenoceptor selective agonist salbutamol induced relaxation with a relatively low potency (pEC(50) = 6.6) and with maximum responses of 80% of that to isoprenaline. ICI118551 competitively antagonized (Schild plot of unity) responses to salbutamol with a high affinity (pA2 = 8.3). CONCLUSIONS: These data suggest that beta-adrenoceptor mediated responses to isoprenaline of the bladder trigone are mediated via both the beta(2)- and beta(3)-adrenoceptor subtypes whilst responses to salbutamol appear to be mediated only via the beta(2)-adrenoceptor.

Identification of beta-adrenoceptor subtypes in lower urinary tract of the female pig.

PURPOSE: We investigated the presence and functional role of beta-adrenoceptor subtypes in the bladder base and proximal urethra of the female pig. MATERIALS AND METHODS: Saturation experiments were done with 7 concentrations (0.25 to 16 nM.) of [(3)H]-dihydroalprenolol (NEN Life Science Products, Boston, Massachusetts). Competition experiments with [(3)H]-dihydroalprenolol were performed with unlabeled antagonists (beta1 selective CGP20712A, beta2 selective ICI118551 and beta3 selective SR59230A). In functional studies concentration-relaxation curves to the beta3-agonist BRL37344 were obtained and antagonist affinities for SR59230A were determined. RESULTS: CGP20712A displaced [(3)H]-dihydroalprenolol with low affinity, suggesting that beta1-adrenoceptors were not present. Displacement with ICI118551 in the bladder base and urethra best fitted a 2-site model with 20% and 28% high affinity sites (beta2), respectively. Displacement experiments with SR59230A in the bladder base demonstrated that 59% of binding sites had high affinity (beta3). In the urethra displacement with SR59230A best fitted a 1-site model but with a pK(i) of 7.2 that was intermediate between that expected for beta2 and beta3-adrenoceptors. In functional studies BRL37344 induced relaxation with pEC50 values of 5.5 and 8, and a maximum relaxation response relative to 30 microM. isoprenaline of 79% and 90% in the bladder base and urethra, respectively. The affinity value of SR59230A for the response to BRL37344 was 7.87 and 7.71 in the bladder base and urethra, respectively, which were intermediate between those of beta2 and beta3-adrenoceptors. CONCLUSIONS: Apparently beta3-adrenoceptors are the predominant beta-adrenoceptor subtype present in the lower urinary tract of the pig.

The role of M2 muscarinic receptor subtypes mediating contraction of the circular and longitudinal smooth muscle of the pig proximal urethra.

PURPOSE: We investigated the characterization of muscarinic receptor subtypes in the female pig urethra. MATERIALS AND METHODS: The affinities of muscarinic antagonists against carbachol responses were calculated in normal and cyclic adenosine monophosphate (cAMP) elevated tissues (contraction with KCl and relaxation with isoprenaline) using longitudinal and transverse strips of urethra. RESULTS: In displacement experiments with 1-quinuclidinyl [phenyl-4-3H] benzilate inhibitory constant (pKi) values of 4-diphenylacetoxyl-N-methyl-piperidine methiodide (DAMP) M3 selective antagonist) and methoctramine (M2 antagonist) indicated the presence of the M2 receptor. In functional studies contraction responses to carbachol were greater in longitudinal than in circular muscle. After cAMP elevation the contraction response increased in circular muscles to the level close to that of longitudinal muscles but did not change significantly in cAMP elevated longitudinal muscle. On normal circular tissues 4-DAMP had high mean affinity (mean apparent pKB value 9.3) but with a Schild slope of less than unity (0.76). Methoctramine competitively antagonized carbachol responses (mean affinity [pA2] value 6.9). On normal longitudinal tissues 4-DAMP and methoctramine competitively antagonized carbachol responses (mean pA2 9.0 and 6.2, respectively). After cAMP elevation in circular tissues mean pA2 values for 4-DAMP (8.7) were significantly lower (p = 0.0015), and those for methoctramine (7.3) were significantly higher (p = 0.0193) than in normal tissues. In longitudinal tissues the mean pA2 value for methoctramine (6.9) was significantly greater than in normal tissues (p <0.0001) but the value for 4-DAMP (8.8) did not alter. CONCLUSIONS: Pig urethra appears to have predominantly M2 muscarinic receptors. Contraction of the normal urethra appears to be predominantly mediated by M2 and M3 receptors in circular muscle but by M3 receptors in longitudinal muscle. After cAMP elevation a contribution to contraction of M2 receptors appeared to be demonstrated in the 2 tissues but the involvement of M2 receptors appeared greater in circular muscle.

The role of beta(3)-adrenoceptors in mediating relaxation of porcine detrusor muscle.

1. beta-adrenoceptors mediate relaxation of bladder detrusor smooth muscle. This study investigates the contribution of beta(3)-adrenoceptors to relaxation of the pig urinary bladder. 2. Cell membranes were prepared from detrusor muscle of the pig bladder dome and competition experiments with [(3)H]-dihydroalprenolol (DHA), a non-selective beta-adrenoceptor antagonist was used as a specific radioligand to determine the presence of beta-adrenoceptor subtypes. In functional experiments, isolated detrusor muscle strips were used to determine the potency of agonists and the affinity of antagonists. 3. In competition binding experiments, CGP20712A (beta(1)-adrenoceptor selective) displaced [(3)H]-DHA from a single binding site with a low affinity. In contrast, displacement data for ICI 118551 (beta(2)-adrenoceptor antagonist) and SR59230A (beta(3)-adrenoceptor antagonist) best fitted a two-site model suggesting a predominant (70%) population of beta(3)-adrenoceptors. 4. In functional studies, isoprenaline and salbutamol (beta(2)-adrenoceptor agonist) relaxed KCl precontracted muscle strips with high potency (pEC(50) 7.7 and 7.2, respectively), whilst CGP12177 and BRL37344 (beta(3)-adrenoceptor agonists) had low potency and were partial agonists. CGP20712A and atenolol (beta(1)-adrenoceptor antagonists) antagonised responses with a low affinity. ICI118551 antagonized responses to isoprenaline and salbutamol with a high affinity (pK(B)=7.8 and 8.7, respectively), but the Schild slopes were low suggesting that responses were mediated by more than one beta-adrenoceptor. The Schild plot for SR59230A was biphasic, apparent pK(B) values for 3 - 10 nM SR59230A being 8.6 and those for 30 nM - 1 microM being 7.7. 5. These data suggest that beta(3)-adrenoceptors are the predominant beta-adrenoceptor subtype present in the pig bladder and that beta-adrenoceptor mediated responses of this tissue are mediated via both the beta(2)- and beta(3)-adrenoceptor subtypes.

The role of M2 muscarinic receptor subtypes in mediating contraction of the pig bladder base after cyclic adenosine monophosphate elevation and/or selective M3 inactivation.

PURPOSE: In the bladder body M2 muscarinic receptors predominate but a smaller population of M3 receptors mediates direct detrusor contraction. M2 receptors have an indirect role by inhibiting cyclic adenosine monophosphate mediated relaxation in the bladder body. We investigated whether a similar mechanism also exists in the bladder base. METHODS: Experiments were performed on pig detrusor muscle. In receptor binding studies using l-quinuclidinyl [phenyl-4-(3)H] benzilate ([(3)H]QNB) (NEN Life Science Products, Inc., Boston, Massachusetts) displacement experiments were performed with subtype selective antagonists to determine the M2-to-M3 receptor ratio. In functional studies the affinity of these antagonists against carbachol induced contractions was calculated in normal tissues and in tissues after cyclic adenosine monophosphate elevation by pre-contraction with KCl and relaxation with isoprenaline, and/or selective M3 inactivation by incubation with 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP) mustard (Sigma Chemical Co., St. Louis, Missouri) in the presence of methoctramine (Sigma Chemical Co.) to protect M2 receptors. RESULTS: In saturation binding studies receptor density was 130.5 of fmol./mg. protein and the dissociation constant for [(3)H]QNB was 0.27 nM. Displacement of [(3)H]QNB by the M3 selective antagonist 4-DAMP and the M2 antagonist methoctramine indicated an M2-to-M3 ratio of about 3:1. In functional studies 4-DAMP and methoctramine caused competitive antagonism of responses with affinity values of 9.5 and 6.3 in normal tissues, and 9.3 and 6.1, respectively, in cyclic adenosine monophosphate elevated tissues, suggesting the involvement of M3 receptors only. In tissues in which M3 receptors were inactivated and cyclic adenosine monophosphate levels were elevated the affinity of 4-DAMP was significantly reduced to 8.5 but that of methoctramine was significantly increased to 6.5, suggesting the involvement of M2 receptors. CONCLUSIONS: The M3 subtype appears to mediate contraction of the normal and cyclic adenosine monophosphate elevated tissues of the bladder base. Involvement of M2 receptors was only noted after selective M3 inactivation and cyclic adenosine monophosphate elevation.