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Objectives: To evaluate the long-term safety (primary objective) and efficacy (secondary objective) of antimuscarinic add-on therapy in patients receiving mirabegron., Methods: During a 2-week screening period, patients (aged ≥20 years, mirabegron treatment for ≥6 weeks, residual overactive bladder symptoms) received mirabegron 50 mg once daily. These patients were subsequently randomized to 52 weeks' treatment with mirabegron 50 mg/day plus an antimuscarinic (solifenacin 5 mg, propiverine 20 mg, imidafenacin 0.2 mg, or tolterodine 4 mg) with the potential to double the antimuscarinic dose (except for tolterodine) at week 8. Safety assessments included treatment-emergent adverse events, vital signs, 12-lead electrocardiograms, post-void residual volume, and laboratory evaluations. Efficacy was assessed using changes from baseline in overactive bladder symptom score total score; overactive bladder questionnaire short form score; micturitions, urgency episodes, urinary incontinence episodes, and urgency urinary incontinence episodes/24 h; mean volume voided per micturition; and number of night-time micturitions., Results: Overall, 80.2% of patients (88.1% women, mean age 65 years) experienced at least one treatment-emergent adverse event, with similar rates for all treatments. The adverse events most commonly reported were dry mouth, nasopharyngitis, and constipation. No marked change was observed in systolic or diastolic blood pressure for any treatment, although pulse rate increased slightly in the mirabegron and propiverine, and mirabegron and tolterodine groups. For all treatments, significant improvements were observed in all efficacy parameters, including overactive bladder symptom score total and questionnaire short form scores., Conclusions: Antimuscarinic add-on therapy is well tolerated and effective after initial treatment with mirabegron in patients with overactive bladder symptoms., (© 2018 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association.)

Objectives: To show the efficacy of propiverine hydrochloride in the management of symptoms of stress urinary incontinence in female patients with mixed-type urinary incontinence., Methods: The study was carried out as a multicenter single-arm clinical trial at 64 institutions in Japan. The participants were female patients aged ≥20 years with mixed-type urinary incontinence. The frequency of stress urinary incontinence and urgency urinary incontinence was evaluated at baseline and 4, 8 and 12 weeks after treatment with propiverine hydrochloride. Subjective symptoms were evaluated using the Overactive Bladder Symptom Score and the International Consultation on Incontinence Questionnaire-Short Form. Functional urethral length and maximum urethral closing pressure were also measured at baseline and 12 weeks after treatment at the institutions where the urethral pressure profile was taken., Results: In total, 49 mixed-type urinary incontinence patients were enrolled in the present study. The number of cases of urgency urinary incontinence was reduced time-dependently, which showed statistically significant differences between baseline and 4, 8 and 12 weeks after treatment. A similar statistically different reduction was also observed for stress urinary incontinence. The mean reduction rates of urgency urinary incontinence and stress urinary incontinence at 12 weeks after treatment were 63.9% and 44.3%, respectively. The total scores of International Consultation on Incontinence Questionnaire-Short Form and Overactive Bladder Symptom Score were gradually reduced, and the differences were statistically significant. Functional urethral length and maximum urethral closing pressure at 12 weeks after treatment did not show any statistical differences compared with those at baseline., Conclusions: Propiverine hydrochloride can be an effective therapeutic option for stress urinary incontinence in patients with mixed-type urinary incontinence., (© 2018 The Japanese Urological Association.)

Objective: To assess fesoterodine treatment in elderly women with overactive bladder with and without hypertension., Methods: Data for 2527 elderly women with overactive bladder symptoms, including urgency urinary incontinence, were pooled from 10 double-blind, placebo-controlled fesoterodine studies., Results: A total of 1523 elderly women (60.3%) had a history of hypertension, and 1004 women (39.7%) had no hypertension history. Overactive bladder symptoms, mean bodyweight and mean body mass index at baseline were significantly higher in women with overactive bladder and hypertension versus those without hypertension (P < 0.05). Statistically significant improvements in overactive bladder symptoms at week 12 were observed for fesoterodine treatment versus placebo in women with hypertension and those without (P < 0.05). The diary-dry rate (no urgency urinary incontinence episodes), the proportion with less than eight micturitions/24 h, overactive bladder symptom bother and health-related quality of life were also statistically significantly improved by fesoterodine treatment in both populations. Incidence of treatment-related adverse events with fesoterodine was similar in women with hypertension (39.3%) and without hypertension (44.6%). Dry mouth and constipation were the most common treatment-related adverse events with fesoterodine in women with hypertension (26.2% and 5.2%, respectively) and without hypertension (30.5% and 8.0%)., Conclusions: A relationship among the severity of overactive bladder symptoms, hypertension and obesity in elderly women is suggested. Fesoterodine provides significantly greater improvements in overactive bladder symptoms and health-related quality of life versus placebo in women with or without hypertension. Hypertension does not appear to affect the efficacy and safety of fesoterodine in elderly women with overactive bladder symptoms, including urgency urinary incontinence., (© 2017 The Japanese Urological Association.)

Objectives: To investigate the efficacy of a once-daily oxybutynin patch for nocturia, and its influence on sleep quality in patients with overactive bladder., Methods: We carried out post-hoc analysis of a phase III, randomized, double-blind, comparative study in which an oxybutynin patch was administered once daily for 12 weeks to Japanese patients with overactive bladder. Patients with a baseline mean of one or more episodes of nocturia per night (data from voiding diaries) were analyzed. The mean number of micturitions, mean voided volume per micturition, mean first voided volume at night, mean sleep duration, and hours of undisturbed sleep were compared between the once-daily oxybutynin patch group and the placebo group. All parameters were expressed as the least squares mean values., Results: The analysis included 576 patients. The number of nocturia episodes decreased by 0.66 in the oxybutynin patch group versus 0.51 in the placebo group (P = 0.0249). Also, the voided volume per nocturnal micturition and the first voided volume at night showed a significant increase in the oxybutynin patch group compared with the placebo group (P = 0.0073 and P = 0.0005, respectively). The hours of undisturbed sleep showed significant prolongation by 76.14 min in the oxybutynin patch group versus 56.07 min in the placebo group (P = 0.0257)., Conclusions: Oxybutynin patch treatment reduces the number of nocturia episodes and prolongs the hours of undisturbed sleep, thus improving sleep quality and sleep-related quality of life in patients with overactive bladder., (© 2015 The Japanese Urological Association.)

Objectives: To investigate patient satisfaction with antimuscarinic treatment of overactive bladder syndrome, and to identify factors having a significant influence on satisfaction., Methods: A cross-sectional questionnaire survey was carried out to assess treatment satisfaction among male and female patients with overactive bladder (age ≥20 years) in the Hokuriku district of Japan. The overactive bladder symptom scores, treatment efficacies, adverse events (dry mouth and constipation), and patient satisfaction scores were investigated and compared among patients using different antimuscarinic therapeutics., Results: In total, 977 survey respondents (52.6% men; mean age 73.6 years) received antimuscarinic treatment. The mean overactive bladder symptom score of these patients was 6.17; in addition, 32.3% patients were satisfied with their treatment, but 33.1% were dissatisfied. Factors having a significant influence on treatment satisfaction were sex (men were less satisfied), efficacy, adverse events and the overactive bladder symptom score. Constipation negatively influenced patient satisfaction to a greater extent than did dry mouth. Patient satisfaction varied according to the drug used. Constipation was less severe with the immediate-release-type agents (imidafenacin and oxybutynin) than with the extended-release-type (propiverine, solifenacin or tolterodine)., Conclusions: Just one-third of Japanese Hokuriku patients with overactive bladder seem to be satisfied with their antimuscarinic treatment. Patient satisfaction is impaired by poor efficacy and the presence of adverse events; furthermore, constipation should be recognized as an adverse event that negatively influences patient satisfaction to a greater extent than dry mouth. Patient satisfaction differs according to the antimuscarinic agent used, with higher patient satisfaction being associated with less severe constipation., (© 2013 The Japanese Urological Association.)

Objective: To evaluate the efficacy of imidafenacin for nocturia and nocturnal polyuria in patients with overactive bladder., Materials and Methods: A stratified analysis was conducted on data from a phase III randomized, double-blind, controlled trial of imidafenacin performed at 158 centers in Japan. The subjects received imidafenacin (0.1 mg) twice daily (group I) or placebo twice daily (group P). The 24-hour urine volume, daytime and nighttime voiding frequency, and volume voided/micturition were evaluated from 3-day voiding diaries recorded every 4 weeks during the 12-week study period. Longitudinal data analysis was performed, with all values expressed as the least squares mean ± standard error., Results: A total of 46 patients (mean age 66.54 ± 9.38 years, 9 men and 37 women) with nocturia and nocturnal polyuria (>33% of urine production at night) were enrolled. Group I (n = 35) and group P (n = 11) showed no baseline differences in the daily voided volume, concomitant diseases, age, or body weight. However, the average daily number of micturitions differed (11.22 ± 2.17 vs 14.45 ± 2.85). Therefore, longitudinal data analysis was performed for each micturition pattern. After 12 weeks of treatment, nighttime micturition was significantly less frequent in group I than in group P (P = .0292), and the nocturnal percentage of 24-hour production was significantly smaller (P = .0053). The interval to the first nighttime void was significantly longer in group I than in group P, but no difference was found in the first nighttime voided volume., Conclusion: The novel antimuscarinic agent, imidafenacin, decreases the number of urinations and reduces nocturnal urine production, thereby improving both nocturia and nocturnal polyuria., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Unlabelled: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Antichollnergic agents are anticipated to diminish storage symptoms, as well as nocturia. Nevertheless, the effect of this treatment on polyuria related to nocturia is not clear. By subgroup analysis of the data set from a phase III clinical trial of antimuscarinic agent for OAB patients in Japan, imidafenacin was found to improve nocturia with a reduction in nocturnal polyuria. This study adds the effects and underlying mechanism of antimuscarinic agents decreasing urine production through inhibition of C-fibre in the bladder of water-leaded rats., Objective: To evaluate the effects and underlying mechanisms of antimuscarinic agents used to decrease in urine production in water-loaded rats., Subjects and Methods: Urine production was measured using a cystostomy catheter in female Sprague-Dawley rats every 2 h. The effect of the antimuscarinic agents atropine, tolterodine and imidafenacin on urine production was investigated under water-loaded conditions, which were induced by i.p. injection of 15 mL saline. Blood samples were collected to determine the levels of antidiuretic hormone (ADH), aldosterone (ALD), atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) before, and 2 and 8 h after, antimuscarinic agent administration. To induce desensitization of C-fibre afferent nerves, resiniferatoxin (RTX)was injected s.c. or intravesically 2 days before experiments., Results: Urine production increased and reached its maximum 2 h after 15 mL saline injection. Imidafenacin and tolterodine decreased urine production in water-loaded rats, but ADH, ALD, ANP and BNP levels were not different between imidafenacin-treated and vehicle-treated rats. The inhibitory effect on urine production was not found in RTX-treated rats. Atropine did not reduce urine production., Conclusion: These results suggest that antimuscarinic agents decrease urine volume through C-fibres in the bladder; thus, antimuscarinics with inhibitory effects on C-fibres could be beneficial for nocturia with nocturnal polyuria., (© 2013 BJU International.)

Objective: To investigate the efficacy and safety of a combination treatment with α(1)-blockers and antimuscarinics for detrusor overactivity in rats., Methods: Rats with detrusor overactivity caused by a cerebral infarction were divided into four groups that received an i.v. administration of tamsulosin (0.1-1000 µg/kg); solifenacin (0.01-0.3 mg/kg); combined low doses of tamsulosin (0.008, 0.1 µg/kg) and solifenacin (0.01 mg/kg); or solifenacin (0.1, 0.3, 1.0 mg/kg) at 1-h intervals during the continuous administration of tamsulosin (0.01 µg/kg/h)., Results: Both tamsulosin alone and solifenacin alone significantly increased bladder capacity in cerebral infarcted rats, but these effects were reduced in rats pretreated with resiniferatoxin. The combined low dose of tamsulosin and solifenacin resulted in a significant increase in bladder capacity compared to mono-administration of 0.01 mg/kg solifenacin (68.8 vs 19.8% of control value, respectively). In the group receiving solifenacin at 1-h intervals, solifenacin dose-dependently decreased bladder contraction duration and a significant reduction in bladder contraction pressure (by 35.0% of control value) was found at the highest dose (1.0 mg/kg). However, no reduction in bladder contraction duration was found even at the highest dose of solifenacin when co-administered with tamsulosin., Conclusion: α(1)-Blockers and antimuscarinic agents have an additive ameliorative effect on detrusor overactivity when co-administered at low doses. α(1)-Blockers prevent the reduction in bladder contraction duration induced by a high-dose administration of antimuscarinic agents., (© 2011 The Japanese Urological Association.)

Purpose: We compared changes in nocturia and sleep related parameters between the anticholinergic solifenacin and placebo in patients with overactive bladder associated with nocturia., Materials and Methods: We performed subgroup analysis of data from a randomized, controlled trial of solifenacin (5 or 10 mg) in Japan. Men and women 20 years old or older with overactive bladder were eligible for study participation. Patients who voided at least once during the night at baseline and who completed efficacy and quality of life assessment at baseline and 12 weeks (treatment end) were included in analysis. We compared placebo with the posttreatment change in nocturia and daytime frequency, volume voided per micturition, sleeping time, hours of undisturbed sleep and sleep related quality of life., Results: Subgroup analysis included 962 patients. Solifenacin 10 mg significantly decreased nocturia episodes by 0.46 episodes (p = 0.0449). Solifenacin 5 and 10 mg significantly increased nighttime volume voided per micturition by 30 and 41 ml (p = 0.0033 and <0.0001, respectively). Compared with placebo (33 minutes) the hours of undisturbed sleep significantly increased by 59 and 60 minutes (p = 0.0196 and 0.0195) in patients with solifenacin 5 and 10 mg, respectively. Significant improvement was observed in sleep related quality of life for solifenacin 5 and 10 mg (each p <0.001). Results must be interpreted with caution due to the exploratory nature of this analysis., Conclusions: Solifenacin 10 mg decreases nocturia episodes. Solifenacin 5 and 10 mg increases nighttime volume voided per micturition and may improve quality of sleep and sleep related quality of life in patients with overactive bladder., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: To assess the efficacy and safety of solifenacin add-on therapy to tamsulosin in lower urinary tract symptoms (LUTS) men with residual overactive bladder (OAB) symptoms despite tamsulosin monotherapy., Methods: In this randomized, multicenter, double-blind study, male LUTS patients aged≥50 years with urgency episodes/24 hours≥2 and micturitions/24 hours≥8 were randomized to 3 groups: 12-weeks tamsulosin plus placebo (TAM+PBO), tamsulosin plus solifenacin 2.5 mg (TAM+SOL), and tamsulosin plus solifenacin 5 mg (TAM+SOL). Changes from baseline to end of treatment in the number of urgency episodes/24 hours (primary endpoint), micturitions, nocturia, urgency incontinence episodes, International Prostate Symptom Scores (IPSS), and Overactive Bladder Symptom Score (OABSS) were compared between the TAM+SOL groups and TAM+PBO. Safety was assessed on adverse events, postvoid residual volume, and maximal urinary flow rate (Qmax.)., Results: Six-hundred thirty-eight men were randomized. Urgency was reduced by 2.2 and 2.4 episodes in the TAM+SOL 2.5 and 5 mg groups, respectively. The TAM+SOL 5 mg group showed significant improvement compared with TAM+PBO (-2.4 vs -1.9, P=.049). The number of micturitions in both TAM+SOL groups were significantly reduced compared with TAM+PBO (both P<.001). IPSS storage symptom score and OABSS significantly improved in both TAM+SOL groups compared with TAM+PBO. Changes in IPSS voiding symptom score and Qmax. were similar in all groups. Four patients (1.9%) in the TAM+SOL 5 mg group had urinary retention, but all recovered after catheterization., Conclusions: In male LUTS patients with residual OAB symptoms despite tamsulosin monotherapy, TAM+SOL showed efficacy on urgency, which represents OAB symptoms and was well tolerated., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Antimuscarinics improve detrusor overactivity. We evaluated the effects and action mechanisms of imidafenacin (Kyorin Pharmaceutical, Tokyo, Japan), a novel therapeutic agent for overactive bladder with antimuscarinic activity, on mediator release from urothelium and detrusor overactivity induced by cerebral infarction., Materials and Methods: Bladder hydrodistention was achieved by intravesical infusion of Krebs solution. Bladder adenosine triphosphate and prostaglandin E(2) were measured in the presence and absence of anticholinergics using luciferin-luciferase assay and enzyme-linked immunoassay, respectively. Cerebral infarction was induced in rats by occluding the left middle cerebral artery. The effects of intravenous imidafenacin on bladder function were examined using cystometry in rats with cerebral infarction and in those pretreated with resiniferatoxin., Results: Increased intravesical adenosine triphosphate and prostaglandin E(2) were shown by induced distention of isolated rat bladders. Imidafenacin and darifenacin (Kemprotec, Middlesbrough, United Kingdom) significantly suppressed the increases in adenosine triphosphate and prostaglandin E(2). Decreased bladder capacity was observed in rats with cerebral infarction. Detrusor overactivity was suppressed with a minimum intravenous dose of 0.001 mg/kg imidafenacin. The effects of imidafenacin were not noted in rats pretreated with resiniferatoxin., Conclusions: Results support the hypothesis or suggest that imidafenacin improves cerebral infarction induced detrusor overactivity by suppressing peripheral C-fibers. This effect is thought to be associated with suppression of the release of adenosine triphosphate and prostaglandin E(2) from the urothelium., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Aims: Suprapontine lesions, such as those resulting from cerebrovascular disease, cause bladder storage dysfunction. Detrusor overactivity (DO) following cerebral infarction may be explained by impairment of the suprapontine regulatory system. However, precise mechanisms underlying DO is not clear. The following studies were undertaken to examine pharmacological and genetic mechanisms of DO in rats., Results and Conclusions: Mechanisms of long-lasting DO in rats with cerebral infarction require signal transfer, which begins with the opening of glutamate receptors at the dorsal pontine tegmentum. DO induced by cerebral infarction has been proven to be accompanied by an increase in c-fos and zif268 expression in the dorsal pontine tegmentum and periaqueductal gray and mediated by the activation of N-methyl-D-aspartate (NMDA) receptors, cyclooxygenase-2 (COX-2), and prostaglandin E synthase (PGES). Therefore, the arachidonic acid cascade is dynamically activated in the brain after brain ischemia. Bladder sensory pathways are potential targets for drugs used to treat various bladder dysfunctions because of their role in storage symptoms (i.e., urgency, frequency) and in triggering reflex bladder activity. Antimuscarinic drugs and alpha(1)-blockers are the main treatments for overactive bladder, a condition caused by neurologic lesions, aging, bladder outlet obstruction, and other pathologies. These drugs affect sensory bladder storage symptoms, suggesting an action on bladder and urethral afferent pathways. Using animal models of DO, we demonstrated that these drugs improved bladder storage function via suppression of C-fiber afferent nerves from the lower urinary tract.

Muscarinic receptor antagonists are used clinically for their therapeutic peripheral effects on bladder function. However, these agents may also act on central muscarinic receptors, especially in individuals with compromised blood-brain barrier function. We compared the effects of atropine and tolterodine, agents that do and do not readily cross the blood-brain barrier, respectively, administered peripherally (intravenous [i.v.]) and centrally (intracerebroventricular [i.c.v.]) on cystometrography in conscious rats after cerebral infarction induced by middle cerebral artery occlusion or sham surgery. We hypothesized that tolterodine would produce greater improvement in bladder capacity and less impairment in bladder contractility and that the effects of both agents would be greater in rats with cerebral infarction and sham-operated rats after peripheral administration, but that tolterodine and atropine would exert similar effects after central administration. Bladder capacity was markedly reduced following cerebral infarction. Low-dose i.v. tolterodine (or=20 nmol/kg) significantly increased bladder capacity but also significantly increased residual volume and decreased bladder contraction pressure. Tolterodine was significantly more efficacious than atropine in increasing bladder capacity, whereas atropine produced significantly greater increases in residual volume and reductions in bladder contraction pressure; these treatment group differences were also observed in sham-operated animals. Tolterodine and atropine administered i.c.v. significantly increased bladder capacity following cerebral infarction or sham surgery; however, this was accompanied by significantly increased residual volume and decreased bladder contraction time. The decrease in bladder contraction time was significantly smaller after tolterodine vs atropine. Peripherally acting muscarinic receptor antagonists may be preferable to centrally acting agents for minimizing adverse events, such as incomplete bladder emptying, even in individuals with compromised blood-brain barrier function.

Purpose: Antimuscarinic drugs increase bladder capacity without prominent side effects such as urinary retention even when administered to patients with mild to moderate bladder outlet obstruction. Some mechanisms might exist in the urethra to compensate for the emptying function of the detrusor after the administration of antimuscarinic drugs. We investigated the influence of the antimuscarinic drug propiverine (Taiho Pharmaceutical, Tokyo, Japan) on urethral function., Materials and Methods: Urethral pressure and rhythmic bladder pressure were simultaneously monitored in urethane anesthetized female Sprague-Dawley rats. Prostaglandin E(2) was continuously administered intravesically or intraurethrally to induce detrusor overactivity. To eliminate the influence of bladder activity and monitor urethral baseline pressure isovolumetric pressure of the urethra was then recorded after cystectomy and ligation of the external urethral meatus. Furthermore, in vitro contractile responses of the urethral circular smooth muscle to field stimulation were examined in the presence of propiverine, tamsulosin (Taiho Pharmaceutical), verapamil, omega-conotoxin and atropine (Sigma)., Results: Intravesical or intraurethral administration of prostaglandin E(2) significantly decreased the bladder contraction interval by 10.7% and 36.0%, respectively. Intra-arterial administration of 2 x 10(2) nM/kg propiverine significantly increased the bladder contraction interval in rats receiving intraurethral prostaglandin E(2) by 81.8% but it had no marked effect on rats receiving intravesical prostaglandin E(2). Significant decreases in urethral baseline pressure were found after propiverine administration. Field stimulation induced contraction was inhibited by propiverine and verapamil but not by tamsulosin, omega-conotoxin or atropine., Conclusions: These results suggest that the inhibitory effects of propiverine are more prominent in rats with detrusor overactivity induced by intraurethral prostaglandin E(2) than by intravesical prostaglandin E(2). Propiverine may compensate for detrusor function by decreasing urethral resistance in the voiding phase.

Purpose: We determined whether the effects of antimuscarinics depend on the suppression of C-fiber bladder afferent nerves. We administered tolterodine intravenously or intravesically., Materials and Methods: To induce C-fiber bladder afferent nerve desensitization resiniferatoxin (RTX) (0.3 mg/kg) was injected subcutaneously in female Sprague-Dawley rats 2 days prior to left middle cerebral artery occlusion (MCAO). As controls, we used rats treated with ethanol and saline vehicle (VEH). Insertion of a polyethylene catheter through the bladder dome and MCAO were performed using halothane anesthesia. The effects of intravenous (0.2 to 2000 nM/kg) or intravesical (0.2 or 2 nM) tolterodine, an antimuscarinic agent, on cystometrography were investigated in conscious rats with a cerebral infarct (CI). Tolterodine was instilled intravesically for 30 minutes and cystometry was repeated., Results: Bladder capacity (BC) was markedly decreased after MCAO in RTX treated (RTX-CI) and VEH treated (VEH-CI) rats. Low tolterodine doses (0.2 or 2 nM/kg) significantly increased BC in VEH-CI rats without increasing residual volume but it had no effects on BC in RTX-CI rats. At the highest dose (2,000 nM/kg) the drug significantly decreased bladder contraction pressure and increased residual volume in RTX-CI and VEH-CI rats. Intravesical administration of tolterodine (0.2 or 2 nM) significantly increased BC in VEH-CI rats. However, tolterodine had no effect on BC in RTX-CI rats., Conclusions: These results suggest that at low doses tolterodine exerts an inhibitory effect on C-fiber bladder afferent nerves, thereby, improving BC during the storage phase.

The influence of muscarinic receptor stimulation and blockade on the central regulation of micturition was evaluated in conscious female rats. Saline was infused into the bladder to induce repeated bladder contractions and voiding. Increasing doses of a muscarinic agonist, oxotremorine-M (OXO-M; 0.01 to 1 microg/rat) or antagonist, atropine (0.1 to 30 microg/rat) were administered. Intrathecal OXO-M (0.1 microg) increased bladder capacity (BC; 85 +/- 17%), but did not change maximal voiding pressure (MVP), pressure threshold (PT), postvoiding intravesical pressure, or voiding efficiency (VE). Intracerebroventricular OXO-M (0.1 microg) increased BC (97 +/- 6%), MVP (45 +/- 19%), PT (158 +/- 49%), and reduced VE (-17 +/- 5%). A larger dose of OXO-M (1 microg, either i.c.v. or i.t.) produced greater changes. These effects were not reproduced by i.v. injections of OXO-M. The effects of OXO-M were blocked by pretreatment with atropine in a dose (1 microg i.c.v. or i.t.), which alone had no effect on voiding parameters. A larger dose of atropine (10 microg) reduced MP (-31 +/- 7% i.c.v. and -34 +/- 6% i.t.) and VE (-21 +/- 3% i.c.v. and -25 +/- 5% i.t.) but increased BC (52 +/- 8% i.c.v.). These results indicate that activation of muscarinic receptors in the brain or spinal cord can suppress voluntary voiding, but also stimulates bladder activity during bladder filling. The muscarinic inhibitory mechanisms do not appear to be tonically active. The effects of atropine (i.c.v. and i.t.) indicate that muscarinic excitatory mechanisms are tonically active. These findings raise the possibility that voiding function is regulated by both inhibitory and excitatory cholinergic mechanisms in the central nervous system.