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Objectives: To report the effect of a selective androgen receptor modulators (SARMs) on the urethral continence mechanisms in a rat model of stress urinary incontinence (SUI) induced by bilateral ovariectomy (OVX). Materials and methods: Female Sprague‐Dawley rats with bilateral OVX were used. Rats were divided into five groups; sham operated, vehicle‐treated OVX, low‐dose SARM‐treated OVX (GSK2849466A: 0.005 mg/kg/day, per os [p.o.]), high‐dose SARM‐treated OVX (GSK2849466A: 0.03 mg/kg/day, p.o.) and dihydrotestosterone (DHT)‐treated OVX (1 mg/kg/day, subcutaneous) groups. After 4 weeks of SARM treatments or 3 weeks of DHT treatment (6 weeks after OVX), rats were subjected to evaluation of the sneeze‐induced continence reflex using microtransducer‐tipped catheter methods, sneeze‐induced leak‐point pressure, and continuous cystometry measurements, followed by histological analyses of urethral tissues. Results: (i) OVX significantly impaired urethral continence function after 6 weeks to induce SUI during sneezing. (ii) Low‐dose SARM treatment restored urethral baseline pressure (UBP) without affecting the amplitude of urethral response during sneezing (A‐URS), partially reversing OVX‐induced SUI during sneezing. (iii) High‐dose SARM treatment reversed decreases in both UBP and A‐URS, more effectively preventing SUI during sneezing. (iv) DHT treatment only restored A‐URS without affecting UBP, partially preventing OVX‐induced SUI during sneezing. (v) The high‐dose SARM treatment induced hypertrophy of the striated and smooth muscle around the urethra. (vi) SARM treatment did not affect bladder function in sham or OVX rats. Conclusion: Treatment with SARMs could be a more effective modality for the treatment of SUI than DHT, without affecting bladder function, by enhancing smooth‐ and striated muscle‐mediated urethral function under stress conditions such as sneezing. [ABSTRACT FROM AUTHOR]

Aims In order to clarify whether an alpha1A/D-adrenoceptor (α1A/D-AR) antagonist, naftopidil, or a phosphodiesterase type 5 (PDE5) inhibitor, tadalafil, prevents bladder wall remodeling after spinal cord injury (SCI), we examined the bladder and urethral activity as well as ischemic and fibrotic changes in the bladder using SCI rats with or without naftopidil or tadalafil treatment. Methods Adult female Sprague-Dawley rats were divided into four groups: (1) normal (spinal cord intact); (2) vehicle SCI; (3) naftopidil SCI; and (4) tadalafil SCI groups. In SCI groups, rats underwent Th9-10 spinal cord transection followed by oral application of vehicle, naftopidil (20 mg/kg/day) or tadalafil (2 mg/kg/day) for 1, 2, 4, 8, and 12 weeks. Bladder and urethral pressures, mRNA levels of fibrosis-related molecules and ischemia markers and the composition of bladder collagen and elastin were evaluated. Results Naftopidil treatment reduced the upregulation of mRNA levels of ischemia and fibrosis markers at the early phase of SCI, and ameliorated the decrease of bladder compliance and voiding efficiency, and the increase of urethral pressure and collagen concentration in the bladder wall at the late phase of SCI. Tadalafil treatment reduced the upregulation of mRNA levels of fibrosis markers, the decrease of bladder compliance and the increase of collagen concentration at the late phase of SCI. Conclusions These results suggest that naftopidil and tadalafil treatments improved the bladder remodeling shown by increased bladder collagen contents after SCI in a different time course. Thus, these treatments could be effective for reducing the SCI-related tissue remodeling in the bladder. Neurourol. Urodynam. 9999:XX-XX, 2016. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose We examined the functional role of endogenous IGF-1 (insulin-like growth factor-1) in the recovery phase of stress urinary incontinence induced by simulated childbirth trauma using an IGF-1 receptor inhibitor. Materials and Methods Simulated birth trauma was induced by vaginal distension in female Sprague Dawley® rats. The IGF-1 receptor antagonist JB-1 (10 and 100 μg/kg per day) or vehicle was continuously delivered from 1 day before vaginal distension for 7 days using subcutaneous osmotic pumps. Seven, 14 and 21 days after vaginal distension the effect of JB-1 treatment was examined by functional analyses, including leak point and urethral baseline pressure, and urethral responses during passive increments in intravesical pressure, as well as molecular analyses in urethral tissues, including phosphorylation of Akt, apoptotic changes and peripheral nerve density using Western blot and immunohistochemistry. Results On functional analyses vehicle treated rats with vaginal distension had significantly decreased leak point and urethral baseline pressure, and urethral responses at 7 days, which recovered to the normal level 14 and 21 days after vaginal distension. In the JB-1 treated vaginal distension group leak point and urethral baseline pressure, and urethral responses were still significantly reduced 21 days after vaginal distension. On molecular analyses JB-1 treatment increased apoptotic cells, induced a significant decrease in phosphorylated Akt and prolonged the decrease of peripheral nerve density in urethral tissues. Conclusions Suppression of endogenous IGF-1 activity delayed recovery from stress urinary incontinence induced by simulated childbirth trauma in rats. Thus, IGF-1 is likely to be an important endogenous mediator for functional recovery from childbirth related stress urinary incontinence. This suggests that IGF-1 could be an effective target for treating stress urinary incontinence in women. [ABSTRACT FROM AUTHOR]

Purpose We investigated the effect of duloxetine, a norepinephrine and serotonin reuptake inhibitor, on the sneeze induced continence reflex and on bladder function in rats with cerebral infarction. Materials and Methods Using urethane anesthesia the effect of duloxetine (1 mg/kg intravenously) on the amplitude of urethral responses during sneezing as well as urethral baseline pressure at the mid urethra was evaluated in normal female adult rats and cerebral infarction rats. Tilt leak point pressure was also measured. In normal and cerebral infarction rats continuous cystometry was evaluated before and after duloxetine injection. Results In cerebral infarction rats urethral baseline pressure was 43% lower than in normal rats but the amplitude of urethral responses during sneezing did not differ in the 2 groups. Duloxetine increased the amplitude of urethral responses during sneezing and urethral baseline pressure by 31% and 21%, respectively, in normal rats but did not affect either in cerebral infarction rats. Also, in cerebral infarction rats leak point pressure was 29% lower compared with normal rats. Duloxetine increased leak point pressure in normal rats but not in cerebral infarction rats. Cerebral infarction reduced intercontraction intervals without affecting the amplitude of bladder contractions compared with normal rats. Duloxetine prolonged intercontraction intervals in cerebral infarction rats but not in normal rats. Conclusions These results suggest that cerebral infarction induces not only bladder overactivity but also stress urinary incontinence, which may account for mixed incontinence in patients with cerebral infarction. After cerebral infarction duloxetine reduced bladder overactivity but failed to enhance active urethral closure mechanisms during sneezing, suggesting that disorganization of the brain network after cerebral infarction might influence the effect of duloxetine on lower urinary tract function. [ABSTRACT FROM AUTHOR]

Purpose: We examined the effect of IGF-1 in a rat model of stress urinary incontinence induced by simulated childbirth trauma. Materials and Methods: Simulated birth trauma was induced by vaginal distension in female Sprague Dawley® rats. Four, 7, 14 and 28 days after distension we performed functional assessment by measuring leak point pressure, urethral baseline pressure and the urethral response during a passive increment in intravesical pressure. The expression of IGF-1 and IGF1R mRNA and protein in damaged tissues was examined by real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry. Thereafter hrIGF-1 (50 and 150 μg/kg per day) was continuously delivered from 1 day before distension using subcutaneous osmotic pumps. Four and 7 days after distension the effect of hrIGF-1 treatment was examined by functional analysis of leak point pressure, urethral baseline pressure and the urethral response as well as Western blot and histological analysis. Results: After 4 and 7 days rats with vaginal distension had significantly decreased leak point pressure, urethral baseline pressure and urethral responses. IGF-1 and IGF1R mRNA and protein levels were significantly increased in urethral and pudendal nerves 4 and 7 days after distension. IGF-1 treated groups showed significant improvement in leak point pressure, urethral baseline pressure and urethral responses 4 and 7 days after distension. Moreover, IGF-1 treatment increased Akt phosphorylation and induced cellular proliferation and antiapoptotic effects in the urethra. Conclusions: IGF-1 treatment accelerated recovery from stress urinary incontinence induced by simulated childbirth trauma in association with activation of the Akt signal transduction pathway in rats. This suggests that IGF-1 has therapeutic potential for stress urinary incontinence in women. [ABSTRACT FROM AUTHOR]

Purpose: Stress urinary incontinence is often seen in postmenopausal women but limited information is available on hormone dependent changes of urethral function. Thus, we examined how ovariectomy and estrogen replacement affect urethral continence mechanisms. Materials and Methods: In female nulliparous Sprague-Dawley® rats under urethane anesthesia after ovariectomy with or without estrogen replacement we measured urethral response amplitude during sneezing, urethral baseline pressure and sneeze induced leak point pressure. Whole urethras were tested for ex vivo urethral properties. Results: Urethral response amplitude during sneezing was significantly decreased in 3 and 6-week ovariectomized rats. Urethral baseline pressure was significantly decreased only in 6-week ovariectomized rats. After estrogen replacement urethral baseline pressure but not urethral response amplitude during sneezing was significantly increased. Neither 3-week ovariectomized nor sham operated rats leaked during sneezing but fluid leakage was observed in 63% of 6-week ovariectomized rats. Estrogen replacement decreased the stress urinary incontinence incidence to 25%. Ex vivo testing revealed a significant increase in middle urethral compliance and a decrease in β stiffness at the proximal and middle urethras in 6-week ovariectomized rats. Conclusions: Results indicate that ovariectomy significantly impairs urethral function from the early stage (3 weeks) but does not induce stress urinary incontinence until the late stage (6 weeks). Also, estrogen replacement restores only the urethral baseline pressure parameter, leading to partial prevention of stress urinary incontinence. Since urethral baseline pressure and urethral response amplitude during sneezing parameters are related to urethral smooth and striated muscle activity, respectively, based on our previous studies, hormone replacement therapy may be partially effective for stress urinary incontinence by enhancing smooth muscle mediated urethral activity under stress conditions such as sneezing. [Copyright &y& Elsevier]

Introduction and hypothesis: This study was conducted to investigate the urethral compensatory mechanisms to maintain urinary continence after pudendal nerve injury. Methods: In naive, acute pudendal nerve transection (PNT) and 4 weeks after PNT (PNT-4w) female rats, leak point pressures (LPPs) during bladder compression were measured before and after the application of hexamethonium (C6), propranolol, and N-nitro- l-arginine-methyl ester ( l-NAME), or terazosin and atropine. Responses to carbachol and phenylephrine of proximal and middle urethral muscle strips from naive and PNT-4w rats were also examined. Results: LPPs were significantly decreased in PNT rats but not in PNT-4w rats. LPPs in PNT rats were significantly increased by C6 or L-NAME while LPPs in PNT-4w rats were significantly decreased by C6, or terazosin and atropine. Excitatory responses to carbachol and phenylephrine in the proximal urethral muscle were significantly larger in PNT-4w rats. Conclusions: These results suggest that α-adrenoceptor and muscarinic receptor-mediated contractility is upregulated in the proximal urethra 4 weeks after PNT. [ABSTRACT FROM AUTHOR]

Purpose: We investigated whether replication defective herpes simplex virus vectors encoding genes of glutamic acid decarboxylase, the γ-aminobutyric acid synthesis enzyme, could suppress detrusor-sphincter dyssynergia in rats with spinal cord injury. Materials and Methods: One week after spinalization herpes simplex virus vectors expressing glutamic acid decarboxylase and green fluorescent protein were injected into the bladder wall. Spinal cord injured rats without herpes simplex virus injection (sham treated) and those injected with LacZ encoding herpes simplex virus vectors served as controls. Three weeks after viral injection we simultaneously recorded urethral and intravesical pressure in awake rats. Results: In the glutamic acid decarboxylase group the urethral pressure increase during bladder contraction was significantly decreased by 77% to 79% compared with that in the sham treated and LacZ groups. Bladder activity and urethral baseline pressure did not differ among the 3 groups. Intrathecal application of the γ-aminobutyric acid-A receptor antagonist bicuculline almost completely reversed the decrease in the urethral pressure increase during bladder contractions while intrathecal saclofen (Tocris Cookson, Ellisville, Missouri), a γ-aminobutyric acid-B receptor antagonist, partially reversed it. In the glutamic acid decarboxylase group the mRNA of glutamic acid decarboxylase 67 was significantly increased in L6-S1 dorsal root ganglia, which is where bladder afferents originate, compared with that in the LacZ group. Conclusions: Herpes simplex virus based glutamic acid decarboxylase gene transfer to bladder afferent pathway may represent a novel approach to detrusor-sphincter dyssynergia in cases of spinal cord injury. [ABSTRACT FROM AUTHOR]

Purpose: Serotonin and norepinephrine reuptake inhibitors such as duloxetine have clinical efficacy for stress urinary incontinence. However, the therapeutic dose of duloxetine is often associated with unwanted side effects. We examined whether combined α2-adrenoceptor antagonists could decrease the duloxetine dose due to synergistic effects. Materials and Methods: We used normal female rats and rats with stress urinary incontinence induced by vaginal distention. Urethral responses were measured using a microtransducer tipped catheter. We evaluated the effect of low dose duloxetine (0.1 mg/kg), α2-adrenoceptor antagonists (idazoxan or yohimbine) and sequential administration of drugs on urethral pressure response amplitude during sneezing and urethral baseline pressure. Sneeze induced leak point pressure was also measured. Results: In normal and vaginally distended rats low dose duloxetine did not alter urethral pressure response amplitude during sneezing but it significantly increased urethral baseline pressure. When low dose duloxetine was co-applied with α2-adrenoceptor antagonists, urethral pressure response amplitude during sneezing was significantly increased. In all 7 vaginally distended rats leakage was observed during sneezing. After low dose duloxetine administration fluid leakage still occurred during sneezing. However, after low dose duloxetine and idazoxan co-administration fluid leakage disappeared in 2 of 7 rats and sneeze induced leak point pressure was significantly increased in the remaining incontinent rats with vaginal distention. Conclusions: Findings support the concept that combination therapy with α2-adrenoceptor antagonists may be an effective, novel strategy to reinforce the clinical efficacy of serotonin and norepinephrine reuptake inhibitors for stress urinary incontinence. [Copyright &y& Elsevier]

Purpose: We investigated the role of α2-adrenoceptors and glutamate mechanisms in the urethral continence reflex in response to abdominal pressure increases. Materials and Methods: Under urethane anesthesia external urethral sphincter electromyogram activity was evaluated in spinal cord transected (T8–T9) female rats during lower abdominal wall compression before and after intravenous application of test drugs. The effects of the N-methyl-D-aspartate glutamate receptor antagonist MK-801 (Sigma®) or the α2-adrenoceptor agonist medetomidine (Tocris Cookson, Ellisville, Missouri) (each 0.03, 0.3 and 3 mg/kg intravenously) on external urethral sphincter activity were examined. A 0.3 mg/kg intravenous dose of the α2-adrenoceptor antagonist idazoxan (Sigma) was then administered before or after the application of 1 mg/kg MK-801 intravenously. In addition, 0.3 mg/kg idazoxan were administered intravenously following the application of 1 mg/kg of the serotonin/norepinephrine reuptake inhibitor duloxetine (Kemprotec, Middlesbrough, United Kingdom) intravenously. Results: MK-801 and medetomidine dose dependently decreased external urethral sphincter activity. Idazoxan significantly increased external urethral sphincter activity by 64% but the increase in activity after idazoxan was abolished by MK-801. On the other hand, idazoxan did not reverse the inhibitory effects of MK-801. In addition, idazoxan significantly potentiated the duloxetine effects on external urethral sphincter activity by 120%. Conclusions: These results indicate that 1) glutamate is a major excitatory neurotransmitter in the urethral continence reflex response to abdominal pressure increases, 2) α2-adrenoceptor activation suppresses external urethral sphincter activity, probably via presynaptic inhibition of glutamate release and 3) the effects of serotonin/norepinephrine reuptake inhibitors are enhanced by α2-adrenoceptor inhibition. Therefore, α2-adrenoceptor antagonists could be beneficial for treating stress urinary incontinence. [Copyright &y& Elsevier]

We investigated the effects of in- trathecal application of GABAA- or GABAB-receptor agonists on detrusor-sphincter dyssynergia (DSD) in spinal cord transection (SCT) rats. Adult female Sprague-Dawley rats were used. At 4 wk after Th9-10 SCT, simultaneous recordings of intravesical pressure and urethral pressure were performed under an awake condition to examine the effect of intrathecal application of GABAA and GABAB agonists (muscimol and baclofen, respectively) or GABAA and GABAB antagonists (bicuculline and saclofen, respectively) at the level of L6-S1 spinal cord. In spinal-intact rats, the effects of bicucul-line and saclofen on bladder and urethral activity were also examined. During urethral pressure measurements, DSD characterized by urethral pressure increases during isovolumetric bladder contractions were observed in 95% of SCT rats. However, after intrathecal application of muscimol or baclofen, urethral pressure showed urethral relaxation during isovolumetric bladder contractions. The effective dose to induce inhibition of urethral activity was lower compared with the dose that inhibited bladder contractions. The effect of muscimol and baclofen was antagonized by intrathecal bicuculline and saclofen, respectively. In spinal-intact rats, intrathecal application of bicucul-line induced DSD-like changes. These results indicate that GABAA- and GABAB-receptor activation in the spinal cord exerts the inhibitory effects on DSD after SCT. Decreased activation of GABAA receptors due to hypofunction of GABAergic mechanisms in the spinal cord might be responsible, at least in part, for the development of DSD after SCT. [ABSTRACT FROM AUTHOR]

Purpose: We investigated the effects of intrathecal application of γ-aminobutyric acid A and B receptor agonists on detrusor overactivity in spinal cord injured rats. Materials and Methods: Adult female Sprague-Dawley rats were used. At 4 weeks after Th9-10 spinal cord transection awake cystometry and recordings of external urethral sphincter electromyogram were performed to examine the effect of intrathecal application of the γ-aminobutyric acid A and B agonists muscimol and baclofen or the γ-aminobutyric acid A and B antagonists bicuculline and saclofen (Tocris Cookson, Ellisville, Missouri), respectively, at the level of the L6-S1 spinal cord. The expression of glutamate decarboxylase 67 mRNA in the L6-S1 spinal cord and dorsal root ganglia was also assessed. Results: Muscimol and baclofen produced a dose dependent inhibition of the number (51% to 73% decrease) and amplitude (35% to 93% decrease) of nonvoiding bladder contractions and a decrease in micturition pressure. The effects of muscimol and baclofen were antagonized by bicuculline and saclofen, respectively. Bursting activity of external urethral sphincter electromyogram was inhibited, corresponding to the inhibition of bladder activity by muscimol and baclofen. Glutamate decarboxylase 67 mRNA levels in the spinal cord and dorsal root ganglia were decreased after spinal cord transection (55% and 84%, respectively). Conclusions: These results indicate that γ-aminobutyric acid A and B receptor activation in the spinal cord inhibits detrusor overactivity. The decrease in glutamate decarboxylase 67 mRNA suggests hypofunction of GABAergic inhibitory mechanisms in the spinal cord. Therefore, stimulation of spinal GABAergic mechanisms could be effective for the treatment of detrusor overactivity after spinal cord injury. [Copyright &y& Elsevier]

OBJECTIVE To investigate the effects of the selective phosphodiesterase (PDE) type 4 inhibitor IC485 and the widely used antimuscarinic drug tolterodine tartrate on bladder activity in rats with bladder outlet obstruction (BOO), as inhibition of PDE4 leads to elevation of intracellular cAMP levels and relaxation of smooth muscle. MATERIALS AND METHODS BOO was induced in female Sprague-Dawley rats by tying a silk ligature around the urethra. Six weeks after inducing BOO, conscious rats were assessed by cystometry with the urethral ligature intact. The effects of IC485 (5, 10 and 50 mg/kg intravenous, i.v.) were examined and compared with those of tolterodine (0.01, 0.1 and 1 mg/kg i.v.). RESULTS IC485 (5–50 mg/kg i.v.) decreased the number and amplitude of non-voiding contractions during the storage phase by 63–88% and 49–83%, respectively; IC485 also increased bladder capacity by 28–37%. There was no change in blood pressure after applying IC485. Tolterodine tartrate (0.1 and 1.0 mg/kg) significantly decreased the number and amplitude of non-voiding contractions by 38–74% and 29–44%, respectively, and increased bladder capacity by 19–51%. Whereas voiding efficiency and maximum voiding pressure were not altered by IC485 at any dose, tolterodine significantly reduced both, by 35–67% and 19–34%, respectively. CONCLUSION Both IC485 and tolterodine tartrate reduced detrusor overactivity in rats with BOO. In addition, doses of IC485 that suppressed non-voiding contractions had no effect on voiding function. Therefore, selective PDE4 inhibitors deserve further study as potential agents for treating detrusor overactivity in patients with BOO. [ABSTRACT FROM AUTHOR]

OBJECTIVE To investigate the effects of anaesthesia on the nitrergic pathway during the micturition reflex in rats. MATERIALS AND METHODS The effects of NG-nitro-l-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, on bladder and urethral activities were evaluated by infusion cystometrography (CMG) and urethral perfusion pressure under isovolumetric conditions in awake or urethane-anaesthetized rats. L-NAME was administered intravenously (i.v.), intrathecally (i.t.), intracerebroventriculary (i.c.v.) or intravesically in normal rats or rats pre-treated with resiniferatoxin, a potent C-fibre afferent neurotoxin. RESULTS L-NAME injected i.v. decreased the intercontraction interval (ICI) in the awake but increased it in the anaesthetized rats. L-NAME injected i.t. increased the ICI in both states and these effects were not apparent after pre-treatment with resiniferatoxin. L-NAME injected i.c.v. decreased the ICI in the awake but increased i.t. in the anaesthetized rats. Intravesical L-NAME decreased the ICI in the awake but not in the anaesthetized rats. L-NAME administered i.v., but not i.t. or i.c.v., increased bladder contraction during CMG. Under isovolumetric conditions, L-NAME administered i.v., but not i.t. or i.c.v., reduced the urethral relaxation without changing bladder contraction. CONCLUSIONS These results indicate that spinal NO release facilitates the mechanoceptive C-fibres, and this facilitatory effect is masked by supraspinal (possibly forebrain) and local inhibitory effects of NO during the micturition reflex in awake rats. Urethane seems to inhibit the supraspinal and local inhibitory effects of NO, resulting in unmasking the facilitatory effect of NO in the spinal cord and brain stem. During the voiding phase, urethral relaxation depends on the peripheral but not the central NO system. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated changes in the urethral closure mechanism under a sneeze induced stress condition in a rat model of birth trauma. Materials and Methods: Four days after vaginal distention induced by balloon catheter inflation in the vagina sneezing was induced while recording intravesical pressure with the rat under urethane anesthesia to evaluate sneeze induced leak point pressure, defined as the lowest pressure inducing fluid leakage from the urethral meatus during sneezing. Sneeze induced responses in the bladder and proximal or mid urethra were also measured using microtip transducer catheters. Results: In 5 sham operated rats no leakage was observed from the urethral meatus during sneezing, which produced an increase in intravesical pressure of up to 34 cm H2O. However, in 5 of 6 rats with vaginal distention leakage during sneezing was observed with a sneeze leak point pressure of 26.2 cm H2O. In the mid urethra microtip transducer catheters revealed that pressure increases during sneezing were greater than those in the bladder but they were significantly decreased in the 5 incontinent vaginal distention rats. However, sneeze induced responses at the proximal urethra, which were similar to those in the bladder, were not different in sham operated and incontinent vaginal distention rats. Conclusions: Sneeze induced stress urinary incontinence in a rat model of birth trauma was caused by decreased active closure mechanisms at the mid urethra without affecting the passive transmission of abdominal pressure in the proximal urethra. [Copyright &y& Elsevier]

To create and evaluate the functional effects of a tissue-engineered sling in an animal model of stress urinary incontinence (SUI). Twenty female Sprague-Dawley rats were divided into four equal groups: a control group (C) had no intervention before the leak-point pressure (LPP) was measured; a denervated group (D) had bilateral proximal sciatic nerve transection (PSNT) and periurethral dissection with no sling placed; group S had concomitant bilateral PSNT and a suburethral sling of small intestinal submucosa (SIS) placed; and group (M) had concomitant bilateral PSNT with implantation of a tissue-engineered sling. The suburethral sling was placed via a transabdominal approach with the sling sutured to the pubic bone. Tissue-engineered slings were prepared with muscle-derived cells obtained via the pre-plate technique and subsequently seeded for 2 weeks on a SIS scaffold. Suburethral slings were implanted 2 weeks before LPP testing, using the vertical-tilt method. Surgically placing a suburethral sling is feasible in the female rat, with few complications. LPPs from both sling groups (S and M) were not significantly different from untreated controls (C). The S, M and C groups all had significantly higher LPPs than group D. Importantly, no rat from either sling group (S and M) had signs of urinary retention. Placing tissue-engineered slings in an animal model of SUI resulted in LPP values that were not significantly different from those in untreated control or SIS (S) groups. These data show that incorporating muscle stem cells into SIS slings does not adversely alter the advantageous mechanical properties of the SIS sling in a model of SUI, and provide the basis for future functional studies of tissue-engineered sling materials with long-term retention. [ABSTRACT FROM AUTHOR]

ABSTRACT: Purpose:: We investigated the contribution of α1-adrenoceptor mechanisms to urethral dysfunction associated with diabetes mellitus (DM) in rats. Materials and Methods:: Eight weeks after streptozotocin injection (65 mg/kg intraperitoneally) the effects of DM on urethral relaxation mechanisms were evaluated with subjects under urethane anesthesia by simultaneous recordings of intravesical pressure in isovolumetric conditions and urethral perfusion pressure (UPP). Results:: In diabetic rats the intravesical pressure thresholds for inducing urethral relaxation and the lowest urethral pressure (UPP nadir) during urethral relaxation were significantly higher by 142% and 86%, respectively, than in normal rats, while baseline UPPs were not significantly different. The mean rate of high frequency oscillations of urethral striated muscle in diabetic rats was also significantly lower by 23% than in normal rats. After α-bungarotoxin treatment (333 μg/kg intravenously) to eliminate striated muscle sphincter contractions the SD of baseline UPPs was significantly larger by 93% than in normal rats. Intravenous administration of terazosin (0.4 mg/kg), an α1-adrenoceptor antagonist, significantly decreased the UPP nadir, intravesical pressure thresholds inducing urethral relaxation and the SD by 41%, 87% and 138%, respectively, in diabetic rats but not in normal rats. In the 2 groups of animals after α-bungarotoxin treatment urethral relaxation during a reflex bladder contraction was inhibited by Nω-nitro-L-arginine (40 mg/kg intravenously), a nitric oxide synthase inhibitor. Conclusions:: During reflex bladder contractions streptozotocin induced diabetic rats showed smooth and striated muscle dysfunctions of the urethra. The inhibition of α1-adrenoceptors, which decreased the UPP nadir and UPP fluctuation, may be useful for treating urethral dysfunction in DM. [Copyright &y& Elsevier]

The purpose of this article is to highlight recent developments in the understanding of the neuropathophysiology of stress urinary incontinence (SUI). The innervation of the urethra and the role of the guarding reflex in maintaining continence will be reviewed and recent animal research regarding the physiological basis of SUI will be discussed. [ABSTRACT FROM AUTHOR]

Urethral closure mechanisms during passive increments in intravesicular pressure (Pves) were investigated using microtip transducer catheters in urethane-anesthetized female rats. After a block of reflex bladder contractions by spinal cord transection at T8-T9, abruptly raising Pves to 20, 40, or 60 cmH2O for 2 min induced a bladder pressure-dependent contractile response in a restricted portion of the middle urethra (12.5-15 mm from the urethral orifice) that was abolished by cutting the pelvic nerves bilaterally. In pelvic nerve-intact rats, the bilateral transection of either the pudendal nerves, the nerves to the iliococcygeous/pubococcygeous muscles, or the hypogastric nerves significantly reduced (49-74%) the urethral reflex response induced by passive Pves increases, and combined transection of these three sets of nerves totally abolished the urethra- closing responses. In spinal cord-intact rats, similar urethral contractile responses were elicited during Pves elevation (20 or 40 cmH2O) and were also eliminated by bilateral pelvic nerve transection. After spinal cord and pelvic nerve transection, leak point pressures, defined as the pressure inducing fluid leakage from the urethral orifice during passive Pves elevation by either bladder pressure clamping in 2.5- cmH2O steps or direct compression of the bladder, were significantly lowered by 30-35% compared with sham-operated (spinal cord- transected and pelvic nerve-intact) rats. These results indicate that 1) passive elevation of Pves can elicit pelvic afferent nerve-mediated contractile reflexes in the restricted portion of the urethra mediated by activation of sympathetic and somatic nerves and 2) bladder-to-urethral reflexes induced by passive Pves elevation significantly contribute to the prevention of stress urinary incontinence. [ABSTRACT FROM AUTHOR]

Aims Intrinsic sphincteric deficiency (ISD) denotes a malfunction of the distal urethral sphincter. Our objective was to produce a durable model of ISD in the rat. Methods Surrounding tissues lateral to the mid-urethra were cauterized to produce sphincteric injury in 24 adult female Sprague-Dawley rats. The rats were divided into four groups of six rats each and followed for 2, 4, 6, and 16 weeks. Sphincteric function was studied by using the vertical tilt table/intravesical pressure clamp model to measure leak point pressures (LPPs). Muscle and nerve damage were assessed with hematoxylin and eosin (H&E) and anti-protein gene product (PGP) 9.5 staining, respectively. As a control, 12 rats underwent a sham operation and subsequent LPP testing at 2, 4, 6, and 16 weeks. Results The mean LPPs of the rats 2, 4, 6, and 16 weeks after cauterization were 18.7 ± 0.8 cm H2O, 27.6 ± 1.6 cm H2O, 24.3 ± 1.7 cm H2O, and 19.1 ± 2.2 cm H2O, respectively. The mean LPPs of the rats 2, 4, 6, and 16 weeks after the sham operation were 49.8 ± 1.3 cm H2O, 51.2 ± 1.5 cm H2O, 51.6 ± 2.0 cm H2O, and 49.7 ± 0.6 cm H2O, respectively. When compared to time-matched control groups, the decreased LPPs in each cauterized group were significantly lower ( P < 0.001). Histological analysis showed muscle damage and fewer nerves in all cauterized groups. Conclusions Cauterization of tissues lateral to the mid-urethra decreased LPP without affecting bladder function. This electrocauterization model produced low LPPs that, after 2 weeks, were maintained for up to 16 weeks. Histology suggests that damage to striated muscle and nerves might have contributed to the change in LPP in this model for ISD. Neurourol. Urodynam. 23:166-171, 2004. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The urethral closure mechanism under a stress condition induced by sneezing was investigated in urethane-anesthetized female rats. During sneezing, while the responses measured by microtip transducer catheters in the proximal and middle parts of the urethra increased, the response in the proximal urethra was almost negligible when the bladder response was subtracted from the urethral response or when the abdomen was opened. In contrast, the response in the middle urethra during sneezing was still observed after subtracting the bladder response or after opening the abdomen. These responses in the middle urethra during sneezing were significantly reduced 80% by bilateral transection of the pudendal nerves and the nerves to the iliococcygeous and pubococcygeous muscles but not by transection of the visceral branches of the pelvic nerves and hypogastric nerves. The sneeze leak point pressure was also measured to investigate the role of active urethral closure mechanisms in maintaining total urethral resistance against sneeze-induced urinary incontinence. In sham-operated rats, no urinary leakage was observed during sneeze, which produced an increase of intravesical pressure up to 37 ? 2.2 cmH2O. However, in nerve-transected rats urinary leakage was observed when the intravesical pressure during sneezing exceeded 16.3 ? 2.1 cmH2O. These results indicate that during sneezing, pressure increases elicited by reflex contractions of external urethral sphincter and pelvic floor muscles occur in the middle portion of the urethra. These reflexes in addition to passive transmission of increased abdominal pressure significantly contribute to urinary continence mechanisms under a sneeze-induced stress condition. [ABSTRACT FROM AUTHOR]

To examine the effects of low-dose insulin or a soluble guanylate cyclase activator (sGC) on lower urinary tract dysfunction (LUTD) in rats with diabetes mellitus (DM). Female Sprague-Dawley rats were divided into non-DM control (N), DM induced by streptozotocin (65 mg/kg), with low-dose insulin (DI), DM with vehicle (D), and DM with sGC (GC) groups. In GC group, BAY 60-2770 (1 mg/kg/day) was orally administered in 6–8 weeks after DM. Voiding assay at 2, 4, and 8 weeks after DM, cystometry, and urethral pressure recordings at 8 weeks of DM were performed. mRNA levels of NO-related markers and cGMP protein levels in the urethra, and ischemia and inflammation markers in the bladder were evaluated by RT-PCR. Moderate levels of high blood glucose were maintained in Group DI versus Group D. The 24-h voided volume was significantly higher in Group D versus Groups N and DI. Non-voiding contractions were significantly greater, and voiding efficiency and urethral pressure reduction were significantly lower in Group D versus Groups N, DI, and GC. Urethral cGMP levels were significantly lower in Group D versus Groups N and GC. mRNA levels of PDE5 in the urethra and ischemia and inflammation markers in the bladder increased in Group D versus Group N or DI was reduced after sGC treatment. DI rats with a lesser degree of bladder and urethral dysfunction might be useful as a slow-progressive DM model. sGC activation could be an effective treatment of LUTD in DM. [ABSTRACT FROM AUTHOR]