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Birth trauma and pelvic injury have been implicated in the etiology of stress urinary incontinence (SUI). This study aimed to assess changes in the biomechanical properties and adrenergic-evoked contractile responses of the rat urethra after simulated birth trauma induced by vaginal distension (VD). Urethras were isolated 4 days after VD and evaluated in our established ex vivo urethral testing system that utilized a laser micrometer to measure the urethral outer diameter at proximal, middle, and distal positions. Segments were precontracted with phenylephrine (PE) and then exposed to intralumenal static pressures ranging from 0 to 20 mmHg to measure urethral compliance. After active assessment, the urethra was rendered passive with EDTA and assessed. Pressure and diameter measurements were recorded via computer. Urethral thickness was measured histologically to calculate circumferential stress-strain response and functional contraction ratio (FCR), a measure of smooth muscle activity. VD proximal urethras exhibited a significantly increased response to PE compared with that in controls. Conversely, proximal VD urethras had significantly decreased circumferential stress and FCR values in the presence of PE, suggesting that VD reduced the ability of the proximal segment to maintain smooth muscle tone at higher pressures and strains. Circumferential stress values for VD middle urethral segments were significantly higher than control values. Histological analyses using antibodies against general (protein gene product 9.5) and sympathetic (tyrosine hydroxylase) nerve markers showed a significant reduction in nerve density in VD proximal and middle urethral segments. These results strongly suggest that VD damages adrenergic nerves and alters adrenergic responses of proximal and middle urethral smooth muscle. Defects in urethral storage mechanisms, involving changes in adrenergic regulation, may contribute to stress urinary incontinence induced by simulated birth trauma. incontinence; innervation; biomechanics; smooth muscle; phenylephfine doi: 10.1152/ajprenal.00299.2009.

In this study, we investigated the effects of bladder outlet obstruction (BOO) on the expression and function of large conductance (BK) and small conductance (SK) [Ca.sup.2+]-activated [K.sup.+] channels in detrusor smooth muscle. The bladder from adult female Sprague-Dawley rats with 6-wk BOO were used. The mRNA expression of the BK channel [alpha]-subunit, [beta]1-, [beta]2-, and [beta]4-subnnits and SK1, SK2, and SK3 channels were investigated using real-time RT-PCR. All subunits except for the BK-[beta]2, SK2, and SK3 channels were predominantly expressed in the detrusor smooth muscle rather than in the mucosa. The mRNA expression of the BK channel [alpha]-subunit was not significantly changed in obstructed bladders. However, the expression of the BK channel [beta]1-subunit and the SK3 channel was remarkably increased in obstructed bladders. On the other hand, the expression of the BK channel [beta]4-subunit was decreased as the severity of BOO-induced bladder overactivity progressed. In detrusor smooth muscle strips from obstructed bladders, blockade of BK channels by iheriotoxin (IbTx) or charybdotoxin (CTx) and blockade of SK channels by apamin increased the amplitude of spontaneous contractions. These blockers also increased the contractility and affinity of these strips for carbachol during cumulative applications. The facilitatory effects elicited by these [K.sup.+] channel blockers were larger in the strips from obstructed bladders compared with control bladders. These results suggest that long-term exposure to BOO for 6 wk enhances the function of both BK and SK types of [Ca.sup.2+]-activated [K.sup.+] channels in the detrusor smooth muscle to induce an inhibition of bladder contractility, which might be a compensatory mechanism to reduce BOO-induced bladder overactivity. bladder outlet obstruction; [Ca.sup.2+]-activated [K.sup.+] channels; spontaneous contraction; muscarinic stimulation doi: 10.1152/ajpregu.00523.2009.

To clarify the role of spinal serotonergic mechanisms in preventing stress urinary incontinence (SUI) during sneezing, we investigated the effect of intrathecal (it) application of 8-OH-DPAT (a 5-[HT.sub.1A] agonist), mCPP (a 5-[HT.sub.2B/2C] agonist), and fluoxetine (a serotonin reuptake inhibitor) using a rat model that can examine the neurally evoked continence reflex during sneezing. Amplitudes of urethral pressure responses during sneezing (A-URS), urethral baseline pressure (UBP) at the midurethra, and sneeze-induced leak point pressure (S-LPP) were measured in normal female adult rats and rats with SUI induced by vaginal distention (VD). In normal rats, 8-OH-DPAT decreased A-URS by 48.9%, whereas mCPP increased A-URS by 33.6%. However, A-URS was not changed after fluoxetine. 8-OH-DPAT, mCPP, or fluoxetine did not alter UBP. The effect of 8-OH-DPAT and mCPP was antagonized by WAY-100635 (it), a selective 5-[HT.sub.1A] antagonist, and RS-102221 (it), a selective 5-[HT.sub.2C] antagonist, respectively. Fluoxetine in the presence of WAY-100635 did not change either A-URS or UBP, but fluoxetine in the presence of RS-102221 decreased A-URS. In VD rats, S-LPP was decreased by 14.6 cm[H.sub.2]0 after 8-OH-DPAT, whereas it was increased by 12.8 cm[H.sub.2]0 after mCPP. However, S-LPP was not changed after fluoxetine. These results indicate that activation of 5-[HT.sub.2C] receptors enhances the active urethral closure reflex during sneezing at the spinal level, whereas 5-[HT.sub.1A] inhibits it and that no apparent changes in the sneeze-induced continence reflex after fluoxetine treatment are due to coactivation of excitatory 5-[HT.sub.2C] receptors and inhibitory 5-HT receptors other than the 5-[HT.sub.1A] subtype. Thus, activation of excitatory 5-HT receptor subtypes such as 5-[HT.sub.2C] could be effective for the treatment of SUI. urinary incontinence; neural pathway; serotonergic reuptake inhibitors; birth trauma doi: 10.1152/ajprenal.00297.2009.

We investigated the effect of duloxetine, a norepinephrine (NE) and serotonin (5-HT) reuptake inhibitor, on the neurally evoked urethral continence reflex induced by sneezing in rats. To clarify the role of noradrenergic and serotonergic mechanisms in preventing stress urinary incontinence (SUI) during sneezing, we examined the effect of duloxetine followed by intrathecal (it) methiothepin maleate (5-HT receptor and [[alpha].sup.1]-adrenoceptor antagonist) or terazosin or idazoxan (selective [[alpha].sup.1]- and [[alpha].sup.2]-adrenoceptor antagonists, respectively). Amplitude of urethral pressure responses during sneezing (A-URS), urethral baseline pressure (UBP) at the midurethra, and sneeze-induced leak point pressure (S-LPP) were measured in normal adult female rats and rats with SUI induced by vaginal distension (VD). In normal and VD rats, intravenous application of duloxetine (1 mg/kg) increased AURS by 35% and 34% and UBP by 21% and 34%, respectively. Sneezing-induced fluid leakage from the urethral orifice was observed in VD rats but not in normal rats. S-LPP was increased from 39.1 to 92.2 cm[H.sub.20] by intravenous duloxetine in incontinent VD rats. Duloxetine-mediated enhancement of A-URS was inhibited by terazosin but not methiothepin maleate (it). In addition, simultaneous intrathecal application of methiothepin and terazosin induced a reduction in A-URS during sneezing, which was not increased by intravenous duloxetine. However, the reduced A-URS after intrathecal application of methiothepin and terazosin returned to the control level when duloxetine (iv) was applied after intrathecal idazoxan administration. These results indicate that duloxetine can prevent SUI by facilitating noradrenergic and serotonergic systems in the spinal cord to enhance the sneeze-induced active urethral closure mechanism. urinary incontinence; neural pathway; adrenergic and serotonergic reuptake inhibitors; birth trauma

We investigated the effects of intrathecal application of [GABA.sub.A]- or [GABA.sub.B]-receptor agonists on detrusor-sphincter dyssynergia (DSD) in spinal cord transection (SCT) rats. Adult female Sprague-Dawley rats were used. At 4 wk after [Th.sub.9-10] SCT, simultaneous recordings of intravesical pressure and urethral pressure were performed under an awake condition to examine the effect of intrathecal application of [GABA.sub.A] and [GABA.sub.B] agonists (muscimol and baclofen, respectively) or [GABA.sub.A] and [GABA.sub.B] antagonists (bicuculline and saclofen, respectively) at the level of [L.sub.6]-[S.sub.1] spinal cord. In spinal-intact rats, the effects of bicuculline 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 bicuculline induced DSD-like changes. These results indicate that [GABA.sub.A]and [GABA.sub.B]-receptor activation in the spinal cord exerts the inhibitory effects on DSD after SCT. Decreased activation of [GABA.sub.A] 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. bladder; urethra; spinal cord; [gamma]-aminobutyric acid; detrusor-sphincter dyssynergia