The functions of the lower urinary tract, to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the bladder, urethra, and external urethral sphincter. During urine storage, the outlet is closed, and the bladder smooth muscle is quiescent. When bladder volume reaches the micturition threshold, activation of a micturition center in the dorsolateral pons (the pontine micturition center) induces a bladder contraction and a reciprocal relaxation of the urethra, leading to bladder emptying. During voiding, sacral parasympathetic (pelvic) nerves provide an excitatory input (cholinergic and purinergic) to the bladder and inhibitory input (nitrergic) to the urethra. These peripheral systems are integrated by excitatory and inhibitory regulation at the levels of the spinal cord and the brain. Injury or diseases of the nervous system, as well as drugs and disorders of the peripheral organs, can produce lower urinary tract dysfunction. In the overactive bladder (OAB) condition, therapeutic targets for facilitation of urine storage can be found at the levels of the urothelium, detrusor muscles, autonomic and afferent pathways, spinal cord, and brain. There is increasing evidence showing that the urothelium has specialized sensory and signaling properties including: (1) expression of nicotinic, muscarinic, tachykinin, adrenergic, bradykinin, and transient receptor potential (TRP) receptors, (2) close physical association with afferent nerves, and (3) ability to release chemical molecules such as adenosine triphosphate (ATP), acetylcholine, and nitric oxide. Increased expression and/or sensitivity of these urothelial-sensory molecules that lead to afferent sensitization have been documented as possible pathogenesis of OAB. Targeting afferent pathways and/or bladder smooth muscles by modulating activity of ligand receptors (e.g., neurokinin, ATP, or beta3-adrenergic receptors) and ion channels (e.g., TRPV1 or K) could be effective to suppress OAB. In the stress urinary incontinence condition, pharmacotherapies targeting the neurally mediated urethral continence reflex during stress conditions such as sneezing or coughing could be effective for increasing the outlet resistance. Therapeutic targets include adrenergic and serotonergic receptors in the spinal cord as well as adrenergic receptors at the urethral sphincter, which can enhance urethral reflex activity during stress conditions and increase baseline urethral pressure, respectively.

Purpose To clarify the functional and molecular mechanisms inducing hyper-excitability of C-fiber bladder afferent pathways after spinal cord injury we examined changes in the electrophysiological properties of bladder afferent neurons, focusing especially on voltage-gated K channels. Materials and Methods Freshly dissociated L6-S1 dorsal root ganglion neurons were prepared from female spinal intact and spinal transected (T9-T10 transection) Sprague Dawley® rats. Whole cell patch clamp recordings were performed on individual bladder afferent neurons. Kv1.2 and Kv1.4 α-subunit expression levels were also evaluated by immunohistochemical and real-time polymerase chain reaction methods. Results Capsaicin sensitive bladder afferent neurons from spinal transected rats showed increased cell excitability, as evidenced by lower spike activation thresholds and a tonic firing pattern. The peak density of transient A-type K+ currents in capsaicin sensitive bladder afferent neurons from spinal transected rats was significantly less than that from spinal intact rats. Also, the KA current inactivation curve was displaced to more hyperpolarized levels after spinal transection. The protein and mRNA expression of Kv1.4 α-subunits, which can form transient A-type K+ channels, was decreased in bladder afferent neurons after spinal transection. Conclusions Results indicate that the excitability of capsaicin sensitive C-fiber bladder afferent neurons is increased in association with reductions in transient A-type K+ current density and Kv1.4 α-subunit expression in injured rats. Thus, the Kv1.4 α-subunit could be a molecular target for treating overactive bladder due to neurogenic detrusor overactivity.

Parameters, such as Q(max) or PVR, obtained from the noninvasive urodynamics were most widely correlated with symptoms and QOL. Despite a large group with strict selection of men with LUTS possibly relating to BPO being studied, only weak association between the symptoms or QOL and objective parameters including urodynamics was confirmed.

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(2+)-activated K(+) 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, beta1-, beta2-, and beta4-subunits and SK1, SK2, and SK3 channels were investigated using real-time RT-PCR. All subunits except for the BK-beta2, 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 beta1-subunit and the SK3 channel was remarkably increased in obstructed bladders. On the other hand, the expression of the BK channel beta4-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 iberiotoxin (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(+) 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(2+)-activated K(+) 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.