Guiming Liu

Time dependent changes in diabetic cystopathy in rats include compensated and decompensated bladder function.

PURPOSEnDiabetic 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.nnnMATERIALS AND METHODSnCystometrograms 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.nnnRESULTSnDiabetes 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).nnnCONCLUSIONSnDiabetic 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.

External Urethral Sphincter Activity in Diabetic Rats

To examine the temporal effects of diabetes on the bladder and the external urethral sphincter (EUS) activity in rats.

Bladder and urethral function in pelvic organ prolapsed lysyl oxidase like‐1 knockout mice

To examine bladder and urethral function in pelvic organ prolapsed lysyl oxidase like‐1 (LOXL1) knockout mice.

Bladder dysfunction in mice with experimental autoimmune encephalomyelitis

The vast majority of patients with multiple sclerosis (MS) develop bladder control problems including urgency to urinate, urinary incontinence, frequency of urination, and retention of urine. Over 60% of MS patients show detrusor-sphincter dyssynergia, an abnormality characterized by obstruction of urinary outflow as a result of discoordinated contraction of the urethral sphincter muscle and the bladder detrusor muscle. In the current study we examined bladder function in female SWXJ mice with different defined levels of neurological impairment following induction of experimental autoimmune encephalomyelitis (EAE), an animal model of central nervous system inflammation widely used in MS research. We found that EAE mice develop profound bladder dysfunction characterized by significantly increased micturition frequencies and significantly decreased urine output per micturition. Moreover, we found that the severity of bladder abnormalities in EAE mice was directly related to the severity of clinical EAE and neurologic disability. Our study is the first to show and characterize micturition abnormalities in EAE mice thereby providing a most useful model system for understanding and treating neurogenic bladder.

Pubo-Urethral Ligament Injury Causes Long-Term Stress Urinary Incontinence in Female Rats: An Animal Model of the Integral Theory

PURPOSEnWe examined the long-term effects of pubo-urethral ligament deficiency as a potential model of stress urinary incontinence compared to an established model of stress urinary incontinence.nnnMATERIALS AND METHODSnA total of 21 female Sprague-Dawley rats were randomly assigned to 1 of 3 groups, including pubo-urethral ligament transection, sham pubo-urethral ligament transection and bilateral pudendal nerve transection. Leak point pressure was measured 28 days later via an implanted suprapubic catheter. After leak point pressure measurement all animals were sacrificed. The pubic arch and pelvic organs were harvested for histological examination. The Wilcoxon rank sum test was used to evaluate differences in leak point pressure among the experimental groups.nnnRESULTSnAt 28 days after pubo-urethral ligament transection mean +/- SD leak point pressure was significantly decreased when comparing pubo-urethral ligament transection and pudendal nerve transection to sham treatment (15.75 +/- 6.46 and 15.10 +/- 4.98 cm H(2)O, respectively, vs 42.56 +/- 11.58, p <0.001). No difference was noted when comparing pubo-urethral ligament transection to pudendal nerve transection (p = 0.76), indicating the long-term durability of pubo-urethral ligament transection on inducing stress urinary incontinence in the female rat. Histological examination of en bloc suprapubic areas demonstrated an absent pubo-urethral ligament in the pubo-urethral ligament transection group, and an intact pubo-urethral ligament in the sham treated and pudendal nerve transection groups.nnnCONCLUSIONSnOur results show that pubo-urethral ligament deficiency in the female rat induces long-term stress urinary incontinence that is comparable to that in the established stress urinary incontinence model via pudendal nerve transection. Our novel rat model could be used to investigate mechanisms of stress urinary incontinence in females, including the role of urethral hypermobility and potential therapeutic interventions for stress urinary incontinence.

Efficacy of a Novel Device for Assessment of Autonomic Sensory Function in the Rat Bladder

PURPOSEnWe 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.nnnMATERIALS AND METHODSnWe 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.nnnRESULTSnSensory 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.nnnCONCLUSIONSnAssessment 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.

Efficacy of Neuroselective and Site-specific Nociceptive Stimuli of Rat Bladder

OBJECTIVEnTo 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.nnnMETHODSnA 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.nnnRESULTSnThe 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.nnnCONCLUSIONnFrequency-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.

Calcineurin and Akt expression in hypertrophied bladder in STZ-induced diabetic rat

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.

Erratum: Bladder and urethral function in pelvic organ prolapsed lysyl oxidase like-1 knockout mice. (BJU Int (2007) 100 (414-418) DOI: 10.1111/j.1464-410X.2007.06929.x)

Liu G, Daneshgari F, Li M et al. Bladder and urethral function in pelvic organ prolapsed lysyl oxidase like-1 knockout mice. BJU Int 2007; 100: 414–418. DOI: 10.1111/j.1464-410X.2007.06929.x Liu G, Li M, Vasanji A, Daneshgari F. Temporal diabetes and diuresis-induced alteration of nerves and vasculature of the urinary bladder in the rat. BJU Int 2010; 107: 1988–1993. DOI: 10.1111/j.1464-410X.2010.09840.x