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Diabetes induces time-dependent alterations in urinary bladders. Long-term diabetes causes an underactive bladder. However, the fundamental mechanisms are still elusive. This study aimed to examine the histological changes and the potential molecular pathways affected by long-term diabetes in the rat bladder. Diabetes was induced in 8-week-old male Lewis rats by streptozotocin, while age-matched control rats received citrate buffer only. Forty-four weeks after diabetes induction, bladders were harvested for histological and molecular analyses. The expressions of proteins related to fibrosis, apoptosis and oxidative stress as well as the cellular signaling pathway in the bladder were examined by immunoblotting. Histological examinations illustrated diabetes caused detrusor hypertrophy and fibrotic changes in the bladder. Immunoblotting analysis demonstrated higher collagen I but lower elastin expression in the bladder in diabetic rats. These were accompanied by an increase in the expression of transforming growth factor-beta1, along with the downregulation of matrix metalloptoteinase-1, and upregulation of tissue inhibitor of metalloproteinase-1. Diabetic rats showed an increase in nitrotyrosine, but decrease in nuclear factor erythroid-related factor 2 (Nrf2) levels in the bladder. Enhanced apoptotic signaling was observed, characterized by increased expression of Bcl-2-associated X protein (Bax), decreased expression of Bcl-2, in the diabetic bladder. The nerve growth factor level was decreased in the diabetic bladder. A significant suppression in the protein expressions of phosphorylated extracellular signal-regulated kinases 1/2 was found in diabetic bladders. This study demonstrated that long-term diabetes caused molecular changes that could promote fibrosis and apoptosis in the bladder. Oxidative stress may be involved in this context., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Enhanced spontaneous contractions are associated with overactive bladder. Elevated levels of reactive oxygen species might contribute to enhanced spontaneous contractions. We investigated the regulation of spontaneous contractions and the effects of hydrogen peroxide (H 2 O 2 ) in intact rat bladder strips. The spontaneous contractions were measured using a tissue bath system. The vehicle or the specific activators/blockers were applied and followed by the application of 0.003 g% H 2 O 2 . The basal tension, amplitude, and frequency of spontaneous contractions were quantified. Nisoldipine and bisindolylmaleimide 1 had no effects on spontaneous contractions. SKF96365 and Y27632 decreased basal tension and amplitude. Ryanodine slightly increased frequency. Both iberiotoxin and NS-1619 increased amplitude. Apamin reduced frequency but increased amplitude. NS-309 inhibited both the amplitude and frequency. The basal tension and amplitude increased when H 2 O 2 was applied. Pretreatment with NS-309 inhibited H 2 O 2 -elicited augmented amplitude and frequency, while pretreatment with Y-27632 inhibited the augmented basal tension. The combined application of NS-309 and Y27632 almost eliminated spontaneous contractions and its augmentation induced by H 2 O 2 . In conclusion, Ca 2+ influx, Rho kinase activation, and SK channel inactivation play important roles in spontaneous contractions in intact bladder strips, whereas only latter two mechanisms may be involved in H 2 O 2 -elicited increased spontaneous contractions.

Diabetes mellitus (DM) is a prevalent chronic disease. Type 1 DM (T1DM) is a metabolic disorder that is characterized by hyperglycemia in the context of absolute lack of insulin, whereas type 2 DM (T2DM) is due to insulin resistance-related relative insulin deficiency. In comparison with T1DM, T2DM is more complex. The natural history of T2DM in most patients typically involves a course of obesity to impaired glucose tolerance, to insulin resistance, to hyperinsulinemia, to hyperglycemia, and finally to insulin deficiency. Obesity is a risk factor of T2DM. Diabetes causes some serious microvascular and macrovascular complications, such as retinopathy, nephropathy, neuropathy, angiopathy and stroke. Urological complications of obesity and diabetes (UCOD) affect quality of life, but are not well investigated. The urological complications in T1DM and T2DM are different. In addition, obesity itself affects the lower urinary tract. The aim of this perspective is to review the available data, combined with the experience of our research teams, who have spent a good part of last decade on studies of association between DM and lower urinary tract symptoms (LUTS) with the aim of bringing more focus to the future scientific exploration of UCOD. We focus on the most commonly seen urological complications, urinary incontinence, bladder dysfunction, and LUTS, in obesity and diabetes. Knowledge of these associations will lead to a better understanding of the pathophysiology underlying UCOD and hopefully assist urologists in the clinical management of obese or diabetic patients with LUTS., (Copyright © 2017 the American Physiological Society.)

Aims: Diabetic bladder dysfunction (DBD) has been extensively studied in animal models of type 1 diabetes. We aimed to examine the functional and morphological alterations of the urinary bladder in a type 2 diabetes model, FVB(db/db) mice., Methods: FVB(db/db) mice and age-matched FVB/NJ control mice were tested at either 12, 24 or 52weeks of age. Body weight, blood glucose and glycated hemoglobin (HbA1c) levels were measured. Bladder function was assessed by measurement of 24-h urination behavior and conscious cystometry. Bladder was harvested for Masson's Trichrome staining and morphometric analysis., Results: The body weights of FVB(db/db) mice were twice as those of FVB/NJ control mice. The blood glucose and HbA1c levels were higher in FVB(db/db) mice at 12 and 24weeks, but not at 52weeks. A significant increase in the mean volume per void, but decrease in the voiding frequency, in FVB(db/db) mice was observed. Cystometry evaluation showed increased bladder capacity, voided volume, and peak micturition pressure in FVB(db/db) mice compared with FVB/NJ mice. Morphometric analysis revealed a significant increase in the areas of detrusor muscle and urothelium in FVB(db/db) mice. In addition, some FVB(db/db) mice, especially males at 12 and 24weeks, showed small-volume voiding during 24-h urination behavior measurement, and detrusor overactivity in the cystometry measurement., Conclusions: The FVB(db/db) mouse, displaying DBD characterized by not only increased bladder capacity, void volume, and micturition pressure, but also bladder overactivity, is a useful model to further investigate the mechanisms of type 2 diabetes-related bladder dysfunction., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Manganese superoxide dismutase (MnSOD) is considered a critical component of the antioxidant systems that protect against oxidative damage. We are interested in the role of oxidative stress in bladder detrusor smooth muscle (SM) in different disease states. In this study, we generated an inducible, SM-specific Sod2(-/-) mouse model to investigate the effects of MnSOD depletion on the function of the bladder. We crossbred floxed Sod2 (Sod2(lox/lox)) mice with mice containing heterozygous knock-in of a gene encoding a tamoxifen-activated Cre recombinase in the SM22α promoter locus [SM-CreER(T2)(ki)(Cre/+)]. We obtained Sod2(lox/lox),SM-CreER(T2)(ki)(Cre/+) mice and injected 8-wk-old males with 4-hydroxytamoxifen to induce Cre-mediated excision of the floxed Sod2 allele. Twelve weeks later, SM-specific deletion of Sod2 and depletion of MnSOD were confirmed by polymerase chain reaction, immunoblotting, and immunohistochemistry. SM-specific Sod2(-/-) mice exhibited normal growth with no gross abnormalities. A significant increase in nitrotyrosine concentration was found in bladder SM tissue of SM-specific Sod2(-/-) mice compared with both wild-type mice and Sod2(+/+), SM-CreER(T2)(ki)(Cre/+) mice treated with 4-hydroxytamoxifen. Assessment of 24-h micturition in SM-specific Sod2(-/-) mice revealed significantly higher voiding frequency compared with both wild-type and SM-specific Cre controls. Conscious cystometry revealed significantly shorter intercontraction intervals and lower functional bladder capacity in SM-specific Sod2(-/-) mice compared with wild-type mice. This novel model can be used for exploring the mechanistic role of oxidative stress in organs rich in SM in different pathological conditions., (Copyright © 2015 the American Physiological Society.)

Objectives: To determine whether diabetes mellitus- and diuresis-induced alterations in the bladder can be reversed in rats., Methods: Male Sprague-Dawley rats were randomly distributed into eight groups (n = 16 per group): 3 weeks and 11 weeks age-matched controls, 3 weeks and 11 weeks after streptozotocin-induced diabetes mellitus, 3 weeks after diabetes mellitus induction then treated with insulin for 8 weeks, 3 weeks and 11 weeks after 5% sucrose-induced diuresis, and 3 weeks after 5% sucrose-induced diuresis followed by removal of 5% sucrose for 8 weeks. Bodyweight, blood glucose and glycated hemoglobin A1c were monitored. At the designated time-points, 24-h urinary habits were examined, and cystometry was carried out in half of the animals. The bladders from the remaining animals were harvested for histological examination, and quantification of smooth muscle, urothelium and collagen components., Results: Insulin treatment reversed hyperglycemia and polyuria in diabetic animals successfully, which was shown by normalization of blood glucose, glycated hemoglobin A1c and 24-h urinary habits. Subsequently, bodyweight, bladder weight and percentage change of bladder components (smooth muscle, collagen, urothelium) in total bladder cross-sectional area were reversed to almost normal levels, and the bladder dysfunction was mostly reversed by 8 weeks of glycemic control, seen in the cystometry study. Similar alterations and reversed effects were seen in diuretic rats without and with 5% sucrose removal, respectively., Conclusions: Short-term (3-week induction) diabetes- and polyuria-induced functional and morphological alterations of the bladder can mostly be reversed in rats., (© 2015 The Japanese Urological Association.)

Diabetes mellitus is well known to cause bladder dysfunction; however, the molecular mechanisms governing this process and the effects on individual tissue elements within the bladder are poorly understood, particularly in type 2 diabetes. A shotgun proteomics approach was applied to identify proteins differentially expressed between type 2 diabetic (TallyHo) and control (SWR/J) mice in the bladder smooth muscle and urothelium, separately. We were able to identify 1760 nonredundant proteins from the detrusor smooth muscle and 3169 nonredundant proteins from urothelium. Pathway and network analysis of significantly dysregulated proteins was conducted to investigate the molecular processes associated with diabetes. This pinpointed ERK1/2 signaling as a key regulatory node in the diabetes-induced pathophysiology for both tissue types. The detrusor muscle samples showed diabetes-induced increased tissue remodeling-type events such as Actin Cytoskeleton Signaling and Signaling by Rho Family GTPases. The diabetic urothelium samples exhibited oxidative stress responses, as seen in the suppression of protein expression for key players in the NRF2-Mediated Oxidative Stress Response pathway. These results suggest that diabetes induced elevated inflammatory responses, oxidative stress, and tissue remodeling are involved in the development of tissue specific diabetic bladder dysfunctions. Validation of signaling dysregulation as a function of diabetes was performed using Western blotting. These data illustrated changes in ERK1/2 phosphorylation as a function of diabetes, with significant decreases in diabetes-associated phosphorylation in urothelium, but the opposite effect in detrusor muscle. These data highlight the importance of understanding tissue specific effects of disease process in understanding pathophysiology in complex disease and pave the way for future studies to better understand important molecular targets in reversing bladder dysfunction., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Objective: To develop and test the efficacy of an implantable bladder electrode device that can be used with the Neurometer electrodiagnostic stimulator to assess fiber-specific afferent bladder sensation in the mouse., Methods: We constructed a ball-tipped platinum electrode and surgically implanted it into the mouse bladder. The Neurometer was connected to the electrode to apply selective nerve fiber stimuli (250 Hz for Aδ fibers and 5 Hz for C fibers) of increasing intensities to the bladder mucosa in the mouse to determine bladder sensory threshold (BST) values. Using 58 female C57BL/6J mice, we measured the temporal and interobserver consistency of BST measurements, the effects of intravesical administration of lidocaine and resiniferatoxin on the BST, and the effects of our device on voiding behavior and bladder mucosal integrity., Results: BST values at 250 and 5 Hz did not vary significantly when measured 2, 4, and 6 days after device implantation, or when obtained by 2 blinded independent observers. Intravesical lidocaine yielded a transient increase in BST values at both 250 Hz and 5 Hz, whereas resiniferatoxin yielded a significant increase only at the 5 Hz stimulus frequency after 24 hours. Moderately increased micturition frequency and decreased volume per void were observed 4 and 6 days after device implantation. Histology revealed mild inflammatory changes in the area of the bladder adjacent to the implanted BST device., Conclusion: Assessment of neuroselective bladder sensation in mice is feasible with our device, which provides reproducible BST values for autonomic bladder afferent nerve fibers., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Diabetic bladder dysfunction (DBD), a prevalent complication of diabetes mellitus (DM), is characterized by a broad spectrum of symptoms including urinary urgency, frequency, and incontinence. As DBD is commonly diagnosed late, it is important to understand the chronic impact of DM on bladder tissues. While changes in bladder smooth muscle and innervation have been reported in diabetic patients, the impact of DM on the specialized epithelial lining of the urinary bladder, the urothelium (UT), is largely unknown. Quantitative polymerase chain reaction analysis and electron microscopy were used to evaluate UT gene expression and cell morphology 3, 9, and 20 wk following streptozotocin (STZ) induction of DM in female Sprague-Dawley rats compared with age-matched control tissue. Desquamation of superficial (umbrella) cells was noted at 9 wk DM, indicating a possible breach in barrier function. One causative factor may be metabolic burden due to chronic hyperglycemia, suggested by upregulation of the polyol pathway and glucose transport genes in DM UT. While superficial UT repopulation occurred by 20 wk DM, the phenotype was different, with significant upregulation of receptors associated with UT mechanosensation (transient receptor potential vanilloid subfamily member 1; TRPV1) and UT autocrine/paracrine signaling (acetylcholine receptors AChR-M2 and -M3, purinergic receptors P2X(2) and P2X(3)). Compromised barrier function and alterations in UT mechanosensitivity and cell signaling could contribute to bladder instability, hyperactivity, and altered bladder sensation by modulating activity of afferent nerve endings, which appose the urothelium. Our results show that DM impacts urothelial homeostasis and may contribute to the underlying mechanisms of DBD.

Diabetes causes significant increases in bladder weight but the natural history and underlying mechanisms are not known. In this study, we observed the temporal changes of detrusor muscle cells (DMC) and the calcineurin (Cn) and Akt expressions in detrusor muscle in the diabetic rat. Male Sprague-Dawley rats were divided into 3 groups: streptozotocin-induced diabetics, 5% sucrose-induced diuretics, and age-matched controls. The bladders were removed 1, 2, or 9weeks after disease induction and the extent of hypertrophy was examined by bladder weights and cross sectional area of DMC. Cn and Akt expression were evaluated by immunoblotting. Both diabetes and diuresis caused significant increases in bladder weight. The mean cross sectional areas of DMC were increased in both diabetic and diuretic animals 1, 2, or 9weeks after disease induction. The expression levels of both the catalytic A (CnA) and regulatory B (CnB) subunits of Cn were increased at 1 and 2weeks, but not at 9weeks. Expression of Akt was similar among control, diabetic, and diuretic rat bladder at all time points. In conclusion, diabetes and diuresis induce similar hypertrophy of detrusor muscle during the first 9weeks, indicating that bladder hypertrophy in the early stage of diabetes is in response to the presence of increased urine output in diabetes. Our results suggest that the Cn, but not the Akt signaling pathway may be involved in the development of bladder hypertrophy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To evaluate the organ specificity of sine wave electrical stimulation of the bladder through assessment of the expression of Fos-immunoreactive (IR) cells in rat spinal cord regions., Methods: A total of 37 female Sprague-Dawley rats were divided into 8 groups: sham stimulation; 5, 250, and 2000 Hz stimulation with 1.5- or 2.0-mA intensity; and a group instilled with capsaicin in the bladder. Using a recently developed bladder sensory threshold device, sine wave electrical stimulation was applied for 90 minutes to the rat bladder. The spinal cord was harvested after the rats were killed. The Fos-IR cells in the spinal regions of the medial dorsal horn, lateral dorsal horn, dorsal commissure, and sacral parasympathetic nucleus were measured. The distributions of the Fos-IR neurons were compared., Results: The maximal expression of Fos-IR cells, induced by 250- and 5-Hz stimulation of the bladder, was found at L6 of the spinal cord and was significantly greater than that in the control group (P<.01). Stimulation with 2000 Hz did not induce any Fos-IR cells. Fos-IR neurons were predominantly seen in the sacral parasympathetic nucleus region in response to 250-Hz stimulation and in the dorsal commissure region in response to 5-Hz stimulation. The number of positive neurons was similar to the number caused by capsaicin instillation., Conclusion: Frequency-specific sine wave electrical stimulation of the rat bladder induced the expression of Fos-IR cells in a neuroselective manner. The bladder sensory threshold device could be used for exploration of the pathophysiology of diseases with disturbances of the afferent pathway of the bladder., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: • To characterize the temporal changes of the nerves and vasculature of the bladder in diabetic rats., Materials and Methods: • A total of 36 Sprague-Dawley rats were divided into three groups: streptozotocin-induced diabetics, 5% sucrose-induced diuretics and age-matched controls. • The characteristics of the nerves and vasculature in the equatorial cross-sectional areas of the bladder were examined by immunofluorescence staining of their specific markers, neurofilament 200 (NF200) and CD31, at 1, 9 or 20 weeks after induction. • The distributions of the nerves and blood vessels were observed and the densities were quantified., Results: • Diabetes caused a significant reduction in body weight. Bladder weight increased in diabetic and diuretic rats, but not in controls. • The total cross-sectional wall area and detrusor muscle area at the equatorial midline were greater in bladders of diabetic and diuretic rats than in controls. • Neurofilament 200-immunoreactive (NF200-IR) nerves were mainly distributed in the detrusor muscle. CD31-immunoreactive blood vessels were mainly distributed in the mucosa/submucosa. • There were no significant differences in the NF200-IR nerve terminal area among control, diabetic and diuretic groups. However nerve density was decreased at 9 and 20 weeks in the muscle, and at 20 weeks in the mucosa/submucosa in diabetic and diuretic animals. • Blood vessel density decreased in the diabetic and diuretic groups at 20 weeks in the muscle., Conclusions: • Diabetes induced time-dependent changes in the density of the nerves and vasculature in the bladder tissues. • Diabetes-related polyuria plays an important role in these changes., (© 2010 THE AUTHORS. BJU INTERNATIONAL © 2010 BJU INTERNATIONAL.)

Purpose: Urinary diversion has been used as a surgical option for some bladder diseases. We developed a urinary diversion model in the rat and examined the effects of urinary diversion on the bladder., Materials and Methods: We distributed female Sprague-Dawley® rats into age matched control, sham urinary diversion and urinary diversion groups. Each group was subsequently evaluated 1 or 8 weeks after urinary diversion or sham operation. Diversion was done by surgical disconnection of the ureters from the bladder and implantation to the uterine cervix. Conscious cystometry was examined. Bladders were harvested for histological examination and quantification of smooth muscle, urothelium and collagen. Vaginal histology was assessed. Bladder muscarinic and purinergic receptor expression was examined., Results: All rats survived the urinary diversion procedure. Bladder weight decreased in the diversion group. Cystometry showed decreased intercontractile interval and voided volume in the urinary diversion group compared to those in the control and sham operated groups. Compliance was decreased in diverted rats. Smooth muscle and urothelium were decreased as a percent of total bladder cross-sectional area. Collagen increased in 1 and 8-week diverted rats vs controls. Histological examination of the vaginal wall revealed mild swelling in 2 rats. Urinary diversion caused decreased muscarinic 3 and ligand gated purinergic 1 receptor expression but no change in muscarinic 2 or ligand gated purinergic 2 receptors., Conclusions: Creating a urinary diversion model by ureterovaginostomy in the rat is feasible. Urinary diversion causes distinct functional and morphometric bladder alterations., (Copyright © 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We developed and tested the efficacy of an implantable bladder device which, when combined with the Neurometer, can be used to assess fiber specific afferent bladder sensation in the rat., Materials and Methods: We developed an implantable bladder device that applies selective nerve fiber stimuli (250 Hz for small myelinated Adelta fibers and 5 Hz for unmyelinated C fibers) to the bladder mucosa in the rat to determine bladder sensory perception threshold values. We performed 3 experiments in 55 female Sprague-Dawley rats to examine the effects of our device on voiding habits, assess the interobserver reliability of the sensory perception threshold and determine the effects of intravesical administration of resiniferatoxin (Sigma) and lidocaine on the sensory perception threshold., Results: Sensory perception threshold values obtained by 2 blinded, independent observers were not different from each other (p = 0.41). Sensory perception threshold values obtained at the 2 stimulation frequencies remained constant for at least 3 weeks after device implantation. A significant increase in sensory perception threshold values after resiniferatoxin instillation was noted at a stimulus frequency of 5 Hz (p = 0.02), whereas intravesical lidocaine led to an immediate increase in the sensory perception threshold at 250 and 5 Hz. Device implantation led to an early decreased voided volume and increased frequency of voids, although these parameters returned to normal after 4 days., Conclusions: Assessment of bladder afferent sensation with our newly developed device is feasible in rats. It provides sensory perception thresholds that appear to be fiber-type selective for autonomic bladder afferent nerves.

Objectives: To examine bladder and urethral function in pelvic organ prolapsed lysyl oxidase like-1 (LOXL1) knockout mice., Materials and Methods: Female parous Loxl1 (-/-) mice in the stable phase of prolapse, and age-matched wild type (WT) mice (six each) had conscious cystometry, leak-point pressure (LPP) testing, and contractile responses assessed of their bladder muscle strips to KCl, electrical-field stimulation, ATP, and carbachol., Results: Loxl1 (-/-) mice voided more frequently and had lower mean (sem) bladder capacity, at 0.10 (0.01) vs 0.20 (0.01) mL, and voiding pressure, at 25.0 (1.90) vs 36.6 (4.04) cmH(2)O, respectively, during cystometry than had WT mice. The LPP was not significantly different between WT and Loxl1 (-/-) mice, at 7.05 (0.81) vs 5.22 (1.23) cmH(2)O, respectively. There were no significant differences between bladder strips from Loxl1 (-/-) mice and WT mice in their responsiveness to various stimuli., Conclusions: Loxl1 (-/-) knockout mice had lower urinary tract dysfunction, most likely due to urethral dysfunction. Loxl1 (-/-) knockout mice can be used as an animal model for pelvic floor disorders. Further studies are needed to characterize the morphological and molecular alterations of the bladder and urethra.

The natural history of diabetes mellitus-induced remodeling of the urinary bladder is poorly understood. In this study, we examined temporal remodeling of the bladder in diabetic and diuretic rats. Male Sprague-Dawley rats were divided into three groups: streptozotocin-induced diabetic, 5% sucrose-induced diuretic, and age-matched control. Micturition and morphometric characteristics were evaluated using metabolic cages and light-microscopic examination of the bladder 4 days and 1, 2, 3, and 9 wk after induction. Digital image analysis was used to quantify equatorial cross-sectional areas of bladder tissue and lumen, as well as relative content of the three primary tissue components: smooth muscle, urothelium, and collagen. Diabetes and diuresis caused significant increases in fluid intake, urine output, and bladder weight. In both groups, progressive increases were observed in lumen area from 4 days to 3 wk after induction and in wall area from 2 to 3 wk after induction. Wall thickness decreased within the first 2 wk in the diabetic and diuretic rats but returned to control at 3 and 9 wk. As a percentage of total cross-sectional area, smooth muscle area increased, urothelium area was unchanged, and collagen area decreased in diabetic and diuretic rats after 2-3 wk compared with control rats. In conclusion, diabetes and diuresis induced similar bladder remodeling. Diabetes-induced diuresis caused adaptive physical changes in rat bladder by 4 days after induction; remodeling was observed by 2-3 wk after induction and remained stable from 3 to 9 wk.

Purpose: Diabetic bladder dysfunction is among the most common and bothersome complications of diabetes mellitus. While bladder filling and voiding problems have been reported, the precise functional changes in diabetic bladders remain unclear. We investigated time dependent changes in bladder function in streptozotocin induced diabetic rats., Materials and Methods: Cystometrograms and detrusor muscle contractility were examined in male age matched control and diabetic Sprague-Dawley rats (Harlan, Indianapolis, Indiana) 3, 6, 9, 12 and 20 weeks after diabetes induction with streptozotocin., Results: Diabetes decreased average body weight and increased bladder weight, capacity and compliance. Peak detrusor leak pressure increased gradually from weeks 3 to 6 to 9 in diabetic rats (mean +/- SEM 47.3 +/- 2.5, 50.8 +/- 3.0 and 56.0 +/- 3.6 cm H(2)O) and in controls (36.9 +/- 1.4, 37.7 +/- 1.5 and 41.6 +/- 1.81 cm H(2)O, respectively). However, at 12 and 20 weeks diabetic rats deviated strongly from this trend with peak detrusor leak pressure decreasing vs controls (41.6 +/- 2.8 and 37.3 +/- 0.9 vs 45.2 +/- 1.7 and 49.6 +/- 1.4 cm H(2)O, respectively) and post-void resting pressures increasing from 9-week levels vs controls (interactions p <0.0001). In contractility studies increased contractile force responses of diabetic animals to carbamylcholine chloride, potassium chloride, adenosine 5'-triphosphate and electric field stimulation peaked at 6 or 9 weeks but at 12 to 20 weeks they generally reverted toward those of controls (carbamylcholine chloride and electrical field stimulation interactions p = 0.0022 and 0.01, respectively)., Conclusions: Diabetic bladders may undergo a transition from a compensated to a decompensated state and transition in the streptozotocin rat model may begin 9 to 12 weeks after induction.

Diabetic bladder dysfunction is a common complication of diabetes mellitus (DM) with poorly understood natural history. This study examined the temporal changes in bladder function 3, 9, 12, and 20 wk after induction of DM by streptozotocin (STZ) in male C57BL/6 mice compared with that in age-matched diabetic mice treated with insulin, 5% sucrose-induced diuretic mice, and sham-treated control mice. Conscious cystometrograms of mice were examined in addition to the measurements of micturition cycle. Diabetes resulted in decreased body weight. Bladder weight, urine output, bladder capacity, and compliance increased in the DM and diuretic groups. Peak voiding pressure (PVP) increased initially in both DM and diuretic mice. However, in DM mice, PVP dropped dramatically at and after 12 wk. Similar changes in the capacity, compliance, and emptying ability of the bladder were seen during the first 9 wk of the diabetes or diuresis, whereas significant decline in the emptying ability of the bladder was only seen in diabetes after 12 wk of disease in mice. Long-term insulin replacement effectively reversed most changes in bladder function. These results suggest that the transition from a compensated to a decompensated bladder dysfunction occurs 9-12 wk after induction of DM in mice by STZ.

Aims: We investigated the effects of 24- and 48-hr storage at 4 degrees C in Krebs solution on the function and morphology of isolated, rat urinary bladders., Methods: Strips of bladder were obtained from eight male Sprague-Dawley rats. Six strips were harvested from each bladder and randomized to storage for 24 or 48 hr at 4 degrees C in Krebs solution or examination immediately after harvest. Contractile responses of the strips to potassium chloride (KCl), electric field stimulation (EFS), adenosine 5'-triphosphate (ATP) and carbamylcholine (CCh) were assessed. Histological examination of the bladder strips was performed. The pO(2), pCO(2), and pH of the solution in each storage container were measured at each storage time point., Results: Cold storage induced a significant decrease in the amplitude of contraction in response to KCl and EFS after 24 or 48 hr of storage compared with control. The response of the bladder strips to ATP and CCh was significantly reduced after 48-hr storage compared with control, but not 24-hr storage. The pO(2) and pCO(2) decreased after cold storage. The pH increased after 24 hr of storage and remained stable between 24 and 48 hr of storage. Histological evaluation of the strips showed tissue swelling after 24 and 48 hr of storage., Conclusions: These results suggest that the morphology and function of bladder strips stored for 24 to 48 hr at 4 degrees C in Krebs solution undergo significant changes. Further studies are needed to assess the allowable time for storage of bladder tissue.

Diabetic bladder dysfunction (DBD) is among the most common and bothersome complications of diabetes mellitus. Autonomic neuropathy has been counted as the cause of DBD. In the present study, we compared the alterations in the neurogenically mediated contractile responses of urinary bladder in rats with streptozocin-induced diabetes, 5% sucrose-induced diuresis, and age-matched controls. Male Sprague-Dawley rats were divided into three groups: 9-wk diabetic rats, diuretic rats, and age-matched controls. Micturition and morphometric characteristics were evaluated using metabolic cage and gross examination of the bladder. Bladder detrusor muscle strips were exposed to either periodic electrical field stimulation (EFS) or to EFS in the presence of atropine, alpha,beta-methylene adrenasine 5'-triphosphate, or tetrodotoxin. The proportions of cholinergic, purinergic, and residual nonadrenergic-noncholinergic (NANC) components of contractile response were compared among the three groups of animals. Diabetes caused a significant reduction of body weight compared with diuresis and controls, although the bladders of diabetic and diuretic rats weighed more than the controls. Both diabetes and diuresis caused significant increase in fluid intake, urine output, and bladder size. Diabetes and diuresis caused similarly increased response to EFS and reduced response to cholinergic component compared with controls. However, the purinergic response was significantly smaller in diuretic bladder strips compared with controls but not in diabetic rats. A residual NANC of unknown origin increased significantly but differently in diabetics and diuretics compared with controls. In conclusion, neurogenically mediated bladder contraction is altered in the diabetic rat. Diabetic-related changes do not parallel diuretic-induced changes, indicating that the pathogenesis of DBD needs further exploration.

Purpose: Diabetes mellitus causes diabetic bladder dysfunction. We identified the pathogenic roles of polyuria and hyperglycemia in diabetic bladder dysfunction in rats. Materials and Methods: A total of 72 female Sprague-Dawley® rats were divided into 6 groups, including age matched controls, and rats with sham urinary diversion, urinary diversion, streptozotocin induced diabetes mellitus after sham urinary diversion, streptozotocin induced diabetes mellitus after urinary diversion and 5% sucrose induced diuresis after sham urinary diversion. Urinary diversion was performed by ureterovaginostomy 10 days before diabetes mellitus induction. Animals were evaluated 20 weeks after diabetes mellitus or diuresis induction. We measured 24-hour drinking and voiding volumes, and cystometry. Bladders were harvested to quantify smooth muscle, urothelium and collagen. We measured nitrotyrosine and Mn superoxide dismutase in the bladder. Results: Diabetes and diuresis caused increases in drinking and voiding volume, and bladder weight. Bladder weight decreased in the urinary diversion group and the urinary diversion plus diabetes group. The intercontractile interval, voided volume and compliance increased in the diuresis and diabetes groups, decreased in the urinary diversion group and further decreased in the urinary diversion plus diabetes group. Total cross-sectional tissue, smooth muscle and urothelium areas increased in the diuresis and diabetes groups, and decreased in the urinary diversion and urinary diversion plus diabetes groups. As a percent of total tissue area, collagen decreased in the diuresis and diabetes groups, and increased in the urinary diversion and urinary diversion plus diabetes groups. Smooth muscle and urothelium decreased in the urinary diversion and urinary diversion plus diabetes groups. Nitrotyrosine and Mn superoxide dismutase increased in rats with diabetes and urinary diversion plus diabetes. Conclusions: Polyuria induced bladder hypertrophy, while hyperglycemia induced substantial oxidative stress in the bladder, which may have a pathogenic role in late stage diabetic bladder dysfunction. [Copyright &y& Elsevier]

Purpose: Diabetes mellitus, a metabolic disorder caused by an absolute or relative deficiency of insulin, is a debilitating and costly disease with multiple serious complications. Lower urinary tract complications are among the most common complications of diabetes mellitus. The most common, bothersome lower urinary tract complication of diabetes mellitus is diabetic cystopathy or diabetic bladder dysfunction. We reviewed the current translational knowledge of diabetic bladder dysfunction. Materials and Methods: We performed a search of the English literature through PubMed®. The key words used were diabetes and bladder dysfunction or cystopathy. Our data and perspective are provided for consideration of the future direction of research. Results: Despite traditional recognition of diabetic bladder dysfunction as a voiding problem characterized by poor emptying and overflow incontinence, recent clinical and experimental evidence indicate storage problems such as urgency and urge incontinence in diabetes mellitus cases. Recent experimental evidence from studies of diabetic bladder dysfunction in small animal models of diabetes mellitus show a temporal effect on diabetic bladder dysfunction. Early phase diabetes mellitus causes compensated bladder function and the late phase causes decompensated bladder function. The temporal theory could plausibly provide the scientific road map to correlate clinical and experimental findings, and identify the role of mechanisms such as polyuria, hyperglycemia, oxidative stress, autonomic neuropathy and decompensation of the bladder contractile apparatus in the creation of clinical and experimental manifestations of diabetic bladder dysfunction. Conclusions: Diabetic bladder dysfunction includes time dependent manifestations of storage and emptying problems. Identifying mechanistic pathways would lead to the identification of therapeutic intervention. [Copyright &y& Elsevier]

Purpose: Diabetes mellitus is a group of debilitating and costly diseases with multiple serious complications. Lower urinary tract complications or diabetic uropathy are among the most common complications of diabetes mellitus, surpassing widely recognized complications such as neuropathy and nephropathy. Diabetic uropathy develops in individuals with types 1 and 2 diabetes, and little is known about the natural history of these common and troublesome complications. Animal models have the potential to reveal mechanisms and aid in the development of treatment strategies. Materials and Methods: We present a review of available animal models of diabetes mellitus relative to their use in the study of diabetic uropathy. Results: Large and small animal models of diabetes mellitus are available. While large animals such as dogs and swine may closely mirror the human disease in size and phenotype, the time between diabetic complication onset and development, and associated husbandry expenditures can make acquiring data on statistically valid sample sizes prohibitively expensive. In contrast, small animal models (rats and mice) have much lower expenditures for a larger number of animals and compressed observation time due to a shorter life span. Also, mice are readily manipulated genetically to facilitate the isolation of the effect of single genes (transgenic and knockout mice). Type 1 diabetes mellitus can be induced chemically with streptozotocin, which is selectively toxic to pancreatic β cells. Type 2 diabetes mellitus models have been developed by selective breeding for hyperglycemia with or without associated obesity. Diabetic uropathy has been noted in several well characterized, predictable animal models of diabetes mellitus. Conclusions: Diabetic uropathy, including diabetic bladder dysfunction, has been more frequently studied in small animals with type I diabetes. The recent availability of transgenic models provides a new opportunity for further studies of diabetic uropathy in mouse models of types I and II diabetes mellitus. [Copyright &y& Elsevier]