Effects of low-intensity extracorporeal shock wave therapy on lipopolysaccharide cystitis in a rat model of interstitial cystitis/bladder pain syndrome.

PURPOSE: To investigate the effect of low-intensity extracorporeal shock wave therapy (LiESWT) on lipopolysaccharide (LPS)-induced cystitis in an animal model of interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: Sprague-Dawley rats were divided into three groups: control, cystitis (LPS group, intravesical injection of LPS (1 mg) twice), and cystitis with LiESWT (LiESWT group). On the third and fourth days, LiESWT was administered (0.12 mJ/mm2, 300 shots each time) on the lower abdomen toward the bladder. On the seventh day, the rats underwent pain assessment and a metabolic cage study. Subsequently, a continuous cystometrogram (CMG) was performed under urethane anaesthesia. Immunohistochemical studies were also performed, including S-100 staining, an immunohistochemical marker of Schwann cells in the bladder. RESULTS: In the LPS group, the pain threshold in the lower abdomen was significantly lower than that in the control group. In the metabolic cage study, the mean voided volume in the LPS group significantly increased. The CMG also revealed a significant decrease in bladder contraction amplitude, compatible with detrusor underactivity in the LPS group. Immunohistochemical studies showed inflammatory changes in the submucosa, increased fibrosis, and decreased S-100 stain-positive areas in the muscle layer of the LPS group. In the LiESWT group, tactile allodynia and bladder function were ameliorated, and S-100 stain-positive areas were increased. CONCLUSION: By restoring nerve damage, LiESWT improved lower abdominal pain sensitivity and bladder function in an LPS-induced cystitis rat model. This study suggests that LiESWT may be a new therapeutic modality for IC/BPS.

Profile of gut microbiota and serum metabolites associated with metabolic syndrome in a remote island most afflicted by obesity in Japan.

Numerous studies have revealed distinct differences in the profiles of gut microbiota between non-obese and obese individuals. To date, however, little is known if any disparities in the community of gut microbiota exist between metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) subjects. We therefore aimed to comprehensively characterize the gut microbiota and circulating metabolites in serum from both MHO and MUO residing in the remote island, Kumejima, where the prevalence of obesity is one of the highest in Japan, and explored possible correlations between the gut microbiota profile and markers of metabolic syndrome. Results revealed that MUO showed significantly higher levels of genera such as g_Succinivibrio, g_Granulicatella, g_Brachyspira, g_Oribacterium and g_Atopobium in comparison to MHO. Moreover, abundance of g_Succinivibrio, g_Brachyspira and g_Atopobium were positively correlated with value of fasting insulin, HOMA-R, circulating triglycerides, diastolic blood pressure, BMI, body weight, waist circumference and HbA1c. In addition, MUO compared to MHO showed an imbalance of serum metabolites, with a significant elevation in 2-oxoisovaleric acid, pyruvic acid, 2-hydroxybutyric acid, and creatine. Our data highlight unmet needs in precision approaches for the treatment of obesity, targeting the gut microbiota profile and serum metabolites in a distinct population affected by obesity.

Influence of cerebral infarction on both bladder and urethral activities and changes after tramadol administration in rats.

AIMS: We investigated the changes in bladder and urethral function after cerebral infarction (CI) and the influence of tramadol on these functions. METHODS: Twenty-eight female Sprague Dawley rats were divided into normal and CI groups. In the awake condition, metabolic cage study and blood pressure were evaluated. Under urethane anesthesia, the intravenous effect of tramadol (0.01-1 mg/kg), which has both µ-opioid receptor stimulation and inhibition of norepinephrine and serotonin reuptake, on continuous cystometry, and simultaneous measurements of bladder and urethral perfusion pressure (UPP) were recorded. Infarcted lesions were examined by staining with triphenyltetrazolium chloride, a marker of mitochondrial enzyme activity. RESULTS: CI rats showed impaired sympathetic activity with Horner's syndrome and lower blood pressure. In metabolic cage study, urinary frequency during the dark phase was increased in CI rats. On bladder activity, in CI rats, the baseline pressure threshold for inducing bladder contractions was significantly lower (p < 0.01), and the intercontraction interval was prolonged after tramadol administration. On urethral activity, the baseline UPP was significantly lower in CI rats than in normal rats and it did not change after tramadol administration. Residual urine rate was significantly increased in normal rats, but not in CI rats. CI rats showed brain infarction including the cortex and hypothalamus, which is a center of the autonomic nervous system. CONCLUSIONS: CI-induced ischemic brain damage results in impairment of both bladder and urethral functions, in addition to decreased sympathetic activity. Bladder overactivity after CI can be improved by tramadol; however, urethral activity cannot be improved by it.

Obesity and Voiding Parameters in a Community-Based Population of Okinawa, Japan: Kumejima Digital Health Project (KDHP).

(1) Background: Evidence has accumulated regarding the etiology of lower urinary tract symptoms associated with obesity and metabolic syndrome. Therefore, the present study aimed to identify which subjectively and objectively measured voiding parameters were associated with obesity in a community-based population. (2) Methods: Voiding parameters on a self-administered questionnaire and a digital self-health monitoring system for urine excretion (s-HMSU) were compared between participants with and without obesity, defined as a body mass index ≥ 25 kg/m2 (n = 30 and 29, respectively), from a community in Okinawa, Japan. Logistic regression analysis was employed to calculate the odds ratios of abnormalities in voiding parameters for the obese group, with the non-obese group serving as a reference. (3) Results: The obese group had odds ratios of 5.17 (95% confidence interval: 1.33−20.0) for shortened hours of undisturbed sleep (<302 min) by s-HMSU and 7.65 (1.88−31.1) for nighttime urinary frequency by a questionnaire after adjusting for age and sex. In addition, the obese group had an adjusted odds ratio of 2.27 (0.76−6.78) for decreased maximum bladder capacity (<212 mL) by s-HMSU. (4) Conclusion: the results of the present study suggest that nocturia and shortened hours of undisturbed sleep are signs of obesity.

Evaluation of the Influence of a History of Childhood Nocturnal Enuresis on Nighttime Urinary Frequency and the Causes of Nocturia in Adults.

OBJECTIVE: To examine whether a history of nocturnal enuresis affects nighttime urinary frequency and to evaluate nocturia etiologies in adults. MATERIALS AND METHODS: A total of 143 participants with at least one episode of nocturia per night were included in this study. The self-reported questionnaire collected data on demographic characteristics, medical history, history of nocturnal enuresis in elementary school, lower urinary tract symptoms, and frequency-volume charts. RESULTS: A history of nocturnal enuresis was observed in 52.4% of participants. However, night-time urinary frequency was significantly lower in participants with a history of nocturnal enuresis in elementary school than in those without such history. On multivariate analysis, a history of nocturnal enuresis was also negatively associated with nighttime urinary frequency (P <.01). There was a collinearity effect between age and nighttime urinary frequency. A history of nocturnal enuresis did not affect the presence of nocturnal polyuria or overactive bladder in participants. However, sleep disturbances were fewer in participants with a history of nocturnal enuresis (odds ratio 0.404). CONCLUSION: A history of nocturnal enuresis might be negatively associated with nighttime urinary frequency due to fewer sleep disturbances. Further, progression of nocturia may depend on conditions, such as age and acquired diseases.

Coexisting congenital mid-ureteral stricture and megaureter due to ureterovesical junction obstruction: A case report.

Congenital mid-ureteral strictures (CMS) are rare. Most congenital strictures occur at the ureteropelvic junction or ureterovesical junction, with mid-ureteral strictures accounting for only 4-5% of all cases of ureteral obstruction in children. Furthermore, there are very few reports of coexisting mid-ureteral stricture and ureterovesical junction obstruction (UVJO). Here, we report a case of coexisting UVJO and CMS. CMS was not detected on preoperative magnetic resonance imaging, and hydronephrosis remained after ureteroneocystostomy. Therefore, MRI was repeated and CMS was diagnosed, for which we performed ureteroureterostomy. Intraoperative retrograde pyelography (RGP) aids definitive diagnosis of UVJO.

Age-associated bladder and urethral coordination impairment and changes in urethral oxidative stress in rats.

AIMS: We examined age-associated changes in bladder and urethral coordination involving the nitric oxide (NO)/soluble guanylyl cyclase (sGC) system, which induces urethral smooth muscle relaxation, and urethral ischemic/oxidative stress changes in rats. MAIN METHODS: Sixteen female Sprague-Dawley rats were divided into young (3 months old) and middle-aged (12-15 months old) groups. Urethral activity was evaluated by simultaneously recording intravesical pressure under isovolumetric conditions and urethral perfusion pressure (UPP) under urethane anesthesia. Sodium nitroprusside (SNP, 0.1 mg/kg), an NO donor, and BAY 41-2272, a novel NO-independent stimulator of sGC (0.1 mg/kg), were administered intravenously to both groups. N-nitro-l-arginine methyl ester hydrochloride (l-NAME, 100 mg/kg) was also injected intravenously, to inhibit NO synthase activity in both groups. Staining for the ischemic marker, hypoxia-inducible factor-1α (HIF-1α), and the oxidative stress markers, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA), was performed on tissue sections of the urethra, in both groups. KEY FINDINGS: Baseline UPP and UPP changes were significantly lower in middle-aged rats than in young rats. After administration of SNP and BAY 41-2272, baseline UPP and UPP nadir were significantly decreased in both groups. After administration of l-NAME, UPP change/bladder contraction amplitude in young rats was still lower than at baseline but was completely restored to control levels in middle-aged rats. Immunoreactivity of HIF-1α, 8-OHdG, and MDA was higher in middle-aged rats than in young rats. SIGNIFICANCE: Age-associated ischemic and oxidative stress in the urethra might be correlated with impairment of the NO/sGC system and with coordination of the bladder and urethra.

Effect of a mobile digital intervention to enhance physical activity in individuals with metabolic disorders on voiding patterns measured by 24-h voided volume monitoring system: Kumejima Digital Health Project (KDHP).

PURPOSE: To evaluate the effect of a mobile digital intervention on voiding patterns, we performed 24-h voided volume monitoring in individuals with metabolic disorders. METHODS: Participants with metabolic disorders were grouped into either the intervention group (n = 17), who had access to a smartphone app (CARADA), or the non-intervention group (n = 11), who did not. Urine monitoring was conducted for 24 h using a novel digital self-health monitoring system for urine excretion (s-HMSU). Body weight, abdominal circumference, blood pressure, and biomarkers were measured. RESULTS: Physical findings and blood test results at baseline and 6 months indicated no significant between-group differences. Night-time frequency did not change between baseline and 6 months in the intervention group but significantly worsened at 6 months in the non-intervention group, as compared to baseline (1.0 ± 0.7 vs. 1.5 ± 0.5, p < 0.05). The change in night-time frequency over 6 months did not differ between the intervention and non-intervention groups. Furthermore, the change in hours of undisturbed sleep over 6 months did not differ between the two groups. However, compared with baseline, nocturnal polyuria index tended to worsen at 6 months in the non-intervention group. CONCLUSION: Our study results suggest that mobile digital intervention might be useful for behavioral therapy to improve night-time frequency and urine production and that s-HMSU might be beneficial for confirming the prevention of progress in individuals with metabolic disorders, which can aid in modifying lifestyle.

Collagen type 1A1, type 3A1, and LOXL1/4 polymorphisms as risk factors of pelvic organ prolapse.

OBJECTIVE: Collagen and elastin are the main components of the female pelvic tissue. We investigated whether single nucleotide polymorphisms (SNPs) of collagen type 1 alpha 1 (COL1A1), collagen type 3 alpha 1 (COL3A1), and lysyl oxidase-like (LOXL) 1 and 4 were associated with the onset of pelvic organ prolapse (POP) in Japanese women. Fifty-two women with POP and 28 women without POP were included. SNPs were identified using the TaqMan® SNP genotyping assay. RESULTS: Age, parity, and lower urinary tract symptoms were significantly higher in the POP group than in the control group. The prevalence of genotypes with rs2862296 polymorphism of LOXL4, an enzyme essential for extracellular matrix remodeling, was different between the POP (26.9% for GG, 51.9% for AG) and control groups (14.8% for GG, 33.3% for AG). However, polymorphisms of COL1A1, COL3A1, and LOXL1 were not related to the onset of POP. In the multivariate logistic regression analysis, age was significantly associated with the occurrence of POP. In the univariate analysis, LOXL4 polymorphism was associated with the onset of POP in Japanese women. The knowledge of acquired risk factors and polymorphisms in the genomic background of patients with POP may help prevent POP via early conservative interventions.

Changes in urethral smooth muscle and external urethral sphincter function with age in rats.

To confirm changes in urethral activity with age, both intravesical pressure and urethral perfusion pressure (UPP) were recorded and external urethral sphincter electromyography (EUS-EMG) was performed. A total of 33 female Sprague Dawley rats aged 3 months (young rats), 12 months (middle-aged rats), and 24 months (aged rats) were used. Bladder activity was evaluated using continuous cystometry. Urethral activity was evaluated by simultaneously recording intravesical pressure and UPP in isovolumetric conditions under urethane anesthesia in each group. Additionally, EUS-EMG activity was monitored under the same conditions. In continuous cystometry, the amplitude of bladder contractions was not different among the three groups; nevertheless, residual urine volume was significantly increased in middle-aged and aged rats, as compared in young rats. With respect to UPP, the change in UPP was significantly smaller in aged rats (60%) and middle-aged rats (64%) than in young rats. Furthermore, the mean amplitude of high-frequency oscillations of the EUS was significantly lower in aged (61%) and middle-aged rats (70%) than in young rats. EUS-EMG revealed EUS bursting activity during voiding with clear active and silent phases in young rats but unclear active and silent phases in aged rats. Masson's trichrome staining of the urethra showed EUS atrophy in aged rats compared to young and middle-aged rats. The results indicate that aging induces two urethral dysfunctions in the urethral smooth muscle and EUS, which may lead to dyscoordination between the urinary bladder and urethra.

Tadalafil Improves Nocturia and Nocturia-Related Quality of Life in Patients with Benign Prostatic Hyperplasia (KYU-PRO Study).

INTRODUCTION: Tadalafil improves lower urinary tract symptoms (LUTS) including nocturia. However, the effect of tadalafil on the nocturia-related quality of life (QoL) is still unknown. OBJECTIVE: The effects of tadalafil on nocturia and nocturia-related QoL were evaluated prospectively in patients with benign prostatic hyperplasia (BPH) as a multicenter study. METHODS: Eligible men were ≥40 years with nocturia ≥2 and a prostate volume ≥20 mL. Patients were asked to complete a self-report questionnaire on the International Prostate Symptom Score (IPSS), the Nocturia Quality of Life questionnaire (N-QoL) and the International Index of Erectile Function 5 (IIEF5). Urinary frequency volume charts (FVCs) were also evaluated. These measures were evaluated at baseline, and after 4, 8, and 12 weeks of tadalafil administration (5 mg once daily). RESULTS: Thirty-one patients with a mean age of 74 years, a mean prostate volume of 31 mL, and a mean prostate-specific antigen level of 2.8 ng/mL were included. Treatment with tadalafil significantly improved their nocturia after 4 weeks, and these improvements were maintained for the 12-week treatment period. Total N-QoL score in new patients and several N-QoL items (inadequate sleep at night and overall bother) in all patients improved significantly after tadalafil treatment. FVCs revealed a significant improvement in the number of hours of undisturbed sleep (HUS) after treatment with tadalafil. No serious adverse events were observed. CONCLUSIONS: This study indicates that tadalafil 5 mg once daily improves nocturia, nocturia-related QoL, and HUS in BPH patients with nocturia. These results suggest that tadalafil can offer a clinically meaningful treatment option for BPH patients with nocturia.

[Therapeutic new targets for stress urinary incontinence in the central nervous system].

Stress urinary incontinence (SUI) is a common and bothersome problem among middle-aged women. However, there are few useful drugs for SUI. Urethral hypermobility and intrinsic sphincter deficiency are two main causes of SUI. Various animal models of SUI, such as vaginal distention, pudendal nerve injury, or ovariectomy, have been developed to study the pathophysiology of SUI. In addition, we have previously reported that cerebral infarction rats also induce SUI. Leak point pressure measurements are the most commonly used methods to evaluate the urethral dysfunction in SUI animal models. Originally, we have developed microtransducer-tipped catheter measurements of urethral activity during sneezing. Previous or our basic research has clarified potential strategies for pharmacotherapy of SUI in the central nervous system. Therapeutic targets include adrenergic and serotonergic (5-HT) receptors in the spinal cord, which stimulate pudendal nerve innervating the external urethral sphincter and/or sympathetic nerve innervating urethral smooth muscle. Activation of α1-adrenoceptors, 5-HT2C, or 5-HT7 receptors enhances the reflex at the spinal cord level whereas pre- or postsynaptic α2-adrenoceptors and/or 5-HT1A receptors inhibit the reflex. We have recently reported that stimulation of the spinal µ-opioid receptors by tramadol also enhances the reflex. Thus, we review the recent advances in basic SUI research and potential targets for pharmacotherapy of SUI in the central nervous system.

[Overview of pharmacological mechanisms controlling micturition in the central nervous system].

The functions of the lower urinary tract, to storage and periodically release urine, are dependent on the activity of smooth and striated muscles in the bladder, urethra and external urethral sphincter. This activity is in turn controlled by neural circuits not only in the periphery, but also in the central nervous system (CNS). During urine storage, the outlet is closed and the bladder smooth muscle is quiescent by the neural control mechanism mainly organized in the spinal cord. When bladder volume reaches the micturition threshold, activation of a micturition center in the dorsolateral pons (the pontine micturition center) induces micturition through activation of sacral parasympathetic (pelvic) nerves. The brain rostral to the pons (diencephalon and cerebral cortex) is also involved in excitatory and inhibitory regulation of the micturition reflex. Various transmitters including dopamine, serotonin, norepenephrine, GABA, excitatory and inhibitory amino acids, opioids and acetylcholine are implicated in the modulation of the micturition reflex in the CNS. Therefore, injury or neurodegenerative diseases of the CNS as well as drugs can produce bladder and urethral dysfunctions such as urinary frequency, urgency and incontinence or inefficient bladder emptying.

A case report of nivolumab-induced myasthenia gravis and myositis in a metastatic renal cell carcinoma patient.

We present a 78-year-old male with renal cell carcinoma who developed myasthenia gravis complicated by myositis after nivolumab administration, which was verified by the presence of antibodies against the acetylcholine receptor. The initial symptom was posterior neck pain, and biochemical examination of blood showed elevated levels of hepatic enzymes and creatine phosphokinase. The level of antibody against the acetylcholine receptor increased 4.1-fold. His condition progressed rapidly resulting in respiratory failure 15 days after conservative therapy.

Concomitant radiotherapy and transarterial chemoembolization reduce skeletal-related events related to bone metastases from renal cell carcinoma.

OBJECTIVES: The purpose of this study was to compare the efficacy of radiotherapy (RT) combined with transcatheter arterial chemoembolization (TACE) with RT alone for the treatment of bone metastases from renal cell carcinoma (RCC). METHODS: We included in this retrospective study 25 RCC patients (28 bone metastases), who were treated with RT at our institution. Patients were divided into two groups: patients treated with RT alone (monotherapy group; n = 17) and those treated with RT combined with TACE (combined therapy group; n = 11). The administered median RT dose was 30 Gy in 10 fractions. Anti-cancer agents used in TACE were cisplatin (median dose, 50 mg) and carboplatin (median dose, 240 mg) for patients with reduced renal function. We evaluated the objective response, post-RT-skeletal-related event (PR-SRE)-free rate, and adverse events associated with treatment for each group. RESULTS: The objective response rates for bone metastases in the monotherapy and combined therapy groups were 33% and 82%, respectively (p = 0.009). The 2-year PR-SRE-free rate in the monotherapy and combined therapy groups was 41.8% and 100%, respectively (p = 0.009). The objective response and PR-SRE-free rates were significantly superior in the combined therapy than in the monotherapy group. There were no significant differences in adverse events or survival between the two groups. CONCLUSION: RT combined with TACE is a promising treatment for bone metastases from RCC, as it results in higher objective response, and PR-SRE-free rates compared with RT alone. KEY POINTS: • Skeletal-related events (SREs) are common in patients with bone metastases from renal cell carcinoma (RCC). • Radiotherapy (RT) provides pain relief in patients with bone metastases from RCC, but rarely achieves objective response. • Combination of RT with transcatheter arterial chemoembolization results in higher objective response and post-RT-SRE-free rates compared with RT alone and is a promising treatment for bone metastases from RCC, as it.

The long-term prognosis of nephropathy in operated reflux.

OBJECTIVE: To investigate the postoperative long-term prognosis and the factors predicting the renal function of patients with reflux nephropathy. As the serum creatinine (s-Cr) level tends to increase during infancy, the degree of reflux and renal parenchymal damage are thought to be more important factors in pediatric patients than in older patients. MATERIALS AND METHODS: This study examined s-Cr, urinary protein, and blood pressure of patients who underwent anti-reflux surgery 10 years before. It also calculated the postoperative estimated glomerular filtration rate (eGFR) and examined the correlation between the eGFR and preoperative factors (age, gender, number of urinary tract infections [UTIs], primary diagnosis, reflux grade, percentage of dimercaptosuccinic acid uptake, degree of renal parenchymal damage, s-Cr abnormality, proteinuria, and hypertension), and analyzed the factors associated with the long-term prognosis. RESULTS: The study population was 51 infants (37 boys and 14 girls). The mean age of the patients before surgery and at the follow-up examination was 3.41 ± 3.61 and 14.63 ± 3.74 years, respectively. After surgery, the s-Cr, urinary protein, and blood pressure values showed (44.7%, 26.7%, and 18.2%, respectively) were abnormal. The postoperative eGFR was a mean 90.27 ± 20.42 ml/min/1.73 m2 and primary correlated with an older age (P = 0.0361), no UTI at the primary diagnosis (P = 0.0044), reflux grade ≥8 (P = 0.0180), degree of renal parenchymal damage (group ≥2b, P < 0.0001), s-Cr abnormality (P < 0.0001), and proteinuria (P = 0.0001) at baseline. A total of 20 patients had chronic kidney disease (CKD; Fig. 1). The multiple regression analysis of these factors revealed that an older age (P = 0.0021), reflux grade ≥8 (P = 0.0134), and degree of renal parenchymal damage (group ≥2b, P < 0.0001) were significantly associated with the long-term postoperative prognosis of reflux nephropathy. Using these three factors, this study derived a multiple regression equation estimating eGFR in the 10th year after surgery (Fig. 1). DISCUSSION: In this study, severe vesico-ureteral reflux (reflux grade ≥8) and severe renal parenchymal damage (group ≥2b) were associated with a long-term decrease in the eGFR. In particular, renal parenchymal damage was closely correlated with the postoperative eGFR; thus, this was clearly a critical factor. The age at surgery showed a better correlation with the postoperative eGFR in the multiple regression analysis; thus, age was regarded as an independent prognostic factor. CONCLUSIONS: The age, reflux grade, and degree of renal parenchymal damage at baseline were factors that affected the long-term postoperative prognosis of reflux nephropathy. Patients with high-grade reflux and severe renal parenchymal damage were more likely to show a reduced CKD level at 10 years after anti-reflux surgery.

Validation of a novel digital health monitoring system to measure the volume of voided urine.

AIM: To validate a novel digital health monitoring system to measure the volume of voided urine. METHODS: Micturition volume was calculated using our novel digital self-health monitoring system of urine excretion (s-HMSU) in 18 participants (16 women and 2 men; average age, 40.8 years), without a history of voiding symptoms. Participants completed a self-reported questionnaire regarding their medical history and water intake during the period of observation, as well as the Core Lower Urinary Tract Symptom Score (CLSS) questionnaire. To assess the reliability of the voided volumes measured using the s-HMSU, the intraclass correlation coefficient (ICC) was calculated between the volume and the change in body weight before and after micturition. RESULTS: The CLSS questionnaire confirmed the absence of urinary system diseases in all participants. The medical history was also negative with the exception of hypertension in one participant. The ICC (1,1) between the measured volume of urine excretion using the s-HMSU and the change in body weight was 0.972 (95% confidence interval, 0.957-0.982). CONCLUSIONS: The s-HMSU system provides a reliable measure of voiding volume and is appropriate for home use. It has the potential to facilitate large-scale clinical research to examine the relationship between medical diseases and voiding dysfunction.

The effect of tramadol on sneeze-induced urethral continence reflex through µ-opioid receptors in the spinal cord in rats.

AIMS: We examined the efficacy of tramadol on the urethral reflex during sneezing, as well as the role of µ-opioid receptors in the spinal cord, in rats. METHODS: Forty-one female Sprague-Dawley rats were used. The rats were divided into normal female rats and rats with vaginal distension (VD), which mimics stress urinary incontinence (SUI) in humans. Under urethane anesthesia, the sneeze-induced amplitude of urethral responses (AUR) and baseline pressure (BP) were examined after intravenous injection of tramadol using a microtransducer-tipped catheter in both rat groups. The effect of intrathecal cyprodime, a selective µ-opioid receptor antagonist, following intravenous tramadol injection was examined in normal rats. The tilt leak point pressure (tilt LPP) after intravenous tramadol injection was also evaluated in both groups. RESULTS: In normal rats, tramadol enhanced the AUR and BP by 33.2% and 19.5%, respectively. Tramadol also increased BP by 13.9% in rats with VD, but it did not change AUR. Intrathecal cyprodime alone did not change AUR, but it decreased BP. However, tramadol-provoked increments in AUR were blocked by intrathecal cyprodime, while BP was recovered to the level that it was before administration of cyprodime. Tramadol was associated with a significant elevation in tilt LPP: 24.8% and 19.5% in normal and VD rats, respectively. CONCLUSIONS: These findings suggest that tramadol effectively enhances the AUR at the spinal level and BP peripherally. Therefore, stimulation of the spinal µ-opioid receptors may be useful for the treatment of SUI.

Role of the serotonergic system in urethral continence reflexes during sneezing in rats.

To clarify the role of serotonin (5-HT) in the prevention of stress urinary incontinence (SUI) during sneezing, we investigated the effect of intraperitoneal application of p-chlorophenylalanine (PCPA; a serotonin synthesis inhibitor) and intravenous application of CP-809101 (a 5-HT2C agonist) or LP44 (a 5-HT7 agonist) using female rats, in which the neurally evoked continence reflex during sneezing was examined. Amplitudes of urethral pressure response during sneezing (A-URS), urethral baseline pressure (UBP) at the middle urethra, and sneeze-induced leak point pressure (S-LPP) were measured in normal female adult rats with or without drug administration. PCPA decreased A-URS by 35.1 cmH2O and UBP by 13.3 cmH2O compared with normal rats. In PCPA-administrated rats, CP-809101 increased A-URS by 24.1 cmH2O and UBP by 15.1 cmH2O, and LP44 also increased A-URS by 20.6 cmH2O and UBP by 11.4 cmH2O compared with rats treated with PCPA alone. SUI was observed with S-LPP of 40.1 cmH2O in PCPA-administrated rats, in which CP-809101 and LP44 increased S-LPP by 28.0 and 15.2 cmH2O, respectively, compared with rats treated with PCPA alone. The effects of CP-809101 and LP44 were antagonized by SB-242084 (a selective 5-HT2C antagonist) and SB-269970 (a selective 5-HT7 antagonist), respectively. These results indicate that activation of 5-HT receptors enhances the active urethral closure reflex during sneezing, at least in part via 5-HT2C and 5-HT7 receptors.

Age-associated urethral dysfunction in urethane-anesthetized rats.

AIMS: We aimed to investigate the age-associated changes in movement coordination between the urinary bladder and the urethra in rats. METHODS: A total of 17 female Sprague-Dawley rats were used. The rats were divided into young (3 months old) and middle-aged (12-15 months old) groups. In both groups, isovolumetric cystometry and urethral perfusion pressure (UPP) measurements were performed under urethane anesthesia. After the rhythmic bladder contractions stabilized, L-arginine, a nitric oxide (NO) substrate (100 mg/kg), was administered intravenously in both groups. Subsequently, N-nitro-L-arginine methyl ester hydrochloride (L-NAME) (50 mg/kg) was injected intravenously to inhibit NO synthase activity in both groups. RESULTS: UPP change, defined as UPP nadir minus baseline UPP, was significantly smaller in middle-aged rats (64%) than in young rats (P < 0.05). The mean amplitude of high-frequency oscillations (HFOs) of the external urethral sphincter was also significantly lower (62%) in middle-aged rats than that in young rats (P < 0.05). Urethral contraction during UPP change was also noted in middle-aged rats. This urethral contraction disappeared after L-arginine administration. UPP nadir during bladder contraction was inhibited by L-NAME in both groups. UPP change was greater in middle-aged rats than in young rats, and 3 out of 9 middle-aged rats showed a detrusor-sphincter dyssynergia pattern after L-NAME. CONCLUSIONS: The results indicated that aging induces dysfunction in movement coordination between the urinary bladder and the urethra. Thus, age-associated urethral dysfunctions may lead to inefficient voiding with increased post-void residual urine volume, which is often observed in elderly populations.