Bladder urothelium possesses a nonneuronal cholinergic system and high density of muscarinic receptors. Impaired afferent signaling(Smith et al. 2014a) due to either reduced acetylcholine release from urothelium or due to changes in the sensitivity and coupling of the suburothelial interstitial cell network is offered as an explanation for UAB phenotype. Agents can either directly mimic the release of acetylcholine in the bladder or act indirectly by inhibiting the metabolism of acetylcholine. Acetylcholine released from parasympathetic nerves together with ATP (Burnstock 2013) at the detrusor neuromuscular synapse mediates detrusor contraction. ATP exerts activation of excitatory purinergic P2X₁ receptors on the detrusor smooth muscle, and inhibitory action on P2Y₁ receptors in cholinergic nerve endings controls the acetylcholine release.

Considering the adverse effect profile of direct acting agonists of acetylcholine, namely, bethanechol, there is a definite incentive for enhancing the action of acetylcholine through indirect means. Distigmine inhibits the enzyme, acetylcholinesterase, and thereby increases the pharmacodynamic half-life of endogenously released ACh. Three times daily treatment of distigmine 5 mg for 4 weeks was recently tested in 27 UAB patients (Bougas et al. 2004). In the phase II trial on UAB patients, distigmine was generally well tolerated by UAB patients. Pressure flow studies were conducted before the initiation of distigmine and at follow-up. Distigmine obviated the need for intermittent self-catheterization in 11 patients and PVR was significantly reduced. Treated patients also showed slight increase in maximum flow rate and detrusor pressure at maximum flow. Apart from cholinesterase inhibition for UAB, drugs that downregulate the expression of acetylcholinesterase can be another alternative option. Antagonists for P2Y1 receptor are known to block the ATP-mediated increase of cholinesterase activity with aging (Choi et al. 2003).

A common trait shared by voiding dysfunctions such as UAB, irrespective of their origin, is dysregulation in synthesis and secretion of neurotrophins (Kim et al. 2005; Nirmal et al. 2014; Wang et al. 2015). Four neurotrophins have been identified in mammalian cells: most notably nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-4/5 (NT-4/5). These target tissue-derived neurotrophins exert their effects upon binding to their high-affinity receptors abundantly expressed in the bladder (Girard et al. 2011) and neuronal circuits regulating micturition function (Garraway et al. 2011). Studies have demonstrated that constitutive expression of NGF and BDNF from urothelium and detrusor smooth muscle cells can promote neuronal survival and maturation (Elmariah et al. 2004; Gonzalez et al. 1999). BDNF interacts with serotoninergic and cholinergic transmission as serotonin reuptake inhibitors increase BDNF levels (Song et al. 2014), and BDNF is known to increase the cholinergic transmission through a presynaptic mechanism (Slonimsky et al. 2003). In a recent study, exogenous expression of BDNF was shown to upregulate the expression of cholinergic genes in the bladder (Kashyap et al. 2014b, 2015).

It is known that NGF activates the cell-surface transmembrane glycoprotein TrkA receptor, whereas BDNF acts via high-affinity receptor tropomyosin-related kinase B (TrkB). TrkB receptor is co-expressed with acetylcholine receptors along the postsynaptic membrane of the neuromuscular junction, and expression is innervation dependent (Funakoshi et al. 1995; Pitts et al. 2006). TrkB signaling was demonstrated to be a key regulator of neuromuscular function as blockade of TrkB signaling (Kulakowski et al. 2011) attenuated the neuromuscular transmission and fragmented postsynaptic acetylcholine receptors. Drugs mimicking BDNF action can therefore be potential drugs for increasing the cholinergic transmission in the bladder of UAB patients.

Studies on animal models of neuropathy showed that TAC-302 a cyclohexenoic-long fatty alcohol derivative was able to enhance the outgrowth of neurites. Chronic oral administration of TAC-302 improved the voiding in diabetic bladder dysfunction with dose-dependent reduction in residual urine volume and increased voided volume in UAB secondary to streptozotocin (STZ)-induced diabetes (Takahisa et al. 2013; Yoshizawaa et al. 2012).

Prostaglandins, namely, PGE2, are synthesized by cyclooxygenase-1 (COX-1) and COX-2 in the bladder, which is released during bladder stretch and believed to be responsible for the spontaneous detrusor contractions (Fry et al. 2004). Instillation of PGE2 was able to reduce the voiding interval in UAB secondary to STZ-induced diabetes mellitus (Nirmal et al. 2014). In similar studies on UAB induced by lumbar canal stenosis (LCS), PGE2 infusion increased the frequency of small-amplitude phasic contractions during the filling phase of cystometry under urethane anesthesia performed 4 weeks after LCS (Fig. 7.2), whereas saline-treated group remained acontractile (Wang et al. 2015). Intravenous injection of sulprostone, a prostaglandin E receptor 3 (EP3) agonist at 2 weeks, reproduced the cystometric changes observed following intravesical PGE2 in 4-week old LCS rats under urethane anesthesia (Wang et al. 2015). In a clinical study, once-weekly intravesical PGE2 (1.5 mg in 20 mL 0.9 % saline) was combined with bethanechol 50 mg four times daily for a total of 6-week therapy of 17 male and 2 female UAB patients (Hindley et al. 2004). Combined therapy only showed limited therapeutic effect over placebo, where majority of the patients included in the trial were reliant on clean intermittent self-catheterization with PVR consistently >300 mL. Overall, studies support PGE2 analogues and EP1 receptor as potential drugs and drug target for UAB, respectively.

It is known that the bladder response to purinergic agents increases with age, whereas the response to cholinergic agents decreases with age (Yoshida et al. 2004). These age-dependent biochemical changes support the rationale of developing drugs acting on purinergic pathway for age-associated disorders such as UAB. A recent study showed that in response to distension, ATP is released through pannexin channels into the lumen (Beckel et al. 2015). Considering that aging is associated with loss of responsiveness to bladder filing (Smith et al. 2012), it is suggested that pannexin functionality is reduced with aging. Drugs that activate pannexin channels such as ATP diphosphohydrolase (apyrase) can be potential drugs for UAB.

TRPV1 and TRPV4 are molecular transducers of hot temperature into neuronal signal. GSK 1016790A is a TRPV4 agonist and its intravesical instillation transiently decreased bladder capacity and voided volume (Aizawa et al. 2012). TRPV4 stimulation in the urothelium is considered to facilitate the micturition reflex by activation of the mechanosensitive, capsaicin-insensitive C-fibers of the primary bladder afferents. Extravesical application of piperine, a TRPV1 agonist to rat bladder, increased afferent input and detrusor contractility (Gevaert et al. 2007). Overall, studies support use of TRPV4 and TRPV1 agonists as a potential therapeutic approach for UAB.

A recent study demonstrated that TRPV1 immunoreactivity in unmyelinated nerve fibers within the urothelium, suburothelial space, and muscle layer of the bladder is co-localized with TRPA1 immunoreactivity (Streng et al. 2008). Activation of TRPA1 by allyl isothiocyanate increased the micturition frequency and reduced the voided volume in rat. Findings support agonism of TRPA1 as a potential approach for improving afferent deficit in UAB.

TRPM8 is a molecular thermal sensor for translating cold temperature into neuronal activity (Lei et al. 2013). It is recognized that cold temperature elicits urgency response in individuals with voiding dysfunction. Since sensory endings in the skin are responsible for perception of thermal cues, their stimulation can be harnessed to improve clinical outcomes. Spraying of menthol that activates TRPM8 decreased the voiding interval, micturition volume, and bladder capacity of rats (Lei et al. 2013), suggesting that topical activation of TRPM8 can be used to improve bladder emptying in UAB patients.

In contrast to agonism of TRP channels, antagonism of cannabinoid receptors is a potential therapeutic approach for increasing afferent input from the bladder and reducing bladder capacity (Dmitrieva and Berkley 2002) in UAB patients. Cannabinoid receptors were suggested to be responsible for the pathogenesis of UAB associated with diabetes (Li et al. 2013), and activity of bladder afferents was reduced following activation of CB1 receptors in mouse bladder (Walczak et al. 2009). Based on available research, we postulate that CB1 antagonist, rimonabant (Pataky et al. 2013), is a potential candidate for repositioning in UAB.

Recent studies reported upregulation of M1 receptor subtype in an animal model of UAB induced by prolonged ischemia (Zhao et al. 2015), which suggests there is compensatory upregulation of receptors that can enhance the release of acetylcholine from nerves innervating the UAB. Presynaptic M1 receptors can facilitate the release of acetylcholine from nerves and thereby facilitate afferent signaling and voiding contraction (Witsell et al. 2012). Application of M1 agonist, cevimeline increased the spontaneous contractions of isolated guinea pig bladder strips (Arisawa et al. 2002). Intravenous administration of cevimeline (0.3 mg/kg or higher) in rats increased the non-voiding contractions, suggesting that the release of various substances, including acetylcholine (ACh) and ATP (Munoz et al. 2011), from bladder urothelium and efferent nerves in the bladder was increased. Oral dosing of cevimeline in rats at 30 mg/kg increased the urine volume, pH, and urinary excretion of Na⁺ and Cl⁻ ions. Xanomeline [3(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine] (Shannon et al. 1994) is another M1 agonist available as a drug candidate for UAB.

Since N-type HVACC are involved in facilitating the release of ACh from parasympathetic nerve terminals in the bladder, drugs that activate these channels can be potential agents for UAB. 4-Aminopyridine (4-AP) sold as Ampyra is known to directly stimulate presynaptic N-type VGCC at the concentration of 0.5 mM and blocks Kv1 family channels at 1 mM concentration (Wu et al. 2009). Ampyra and similar drug fampridine (Cardenas et al. 2014) can potentiate the release of neurotransmitters from both sensory and motor nerve terminals and improve neuromuscular function in patients with spinal cord injury, myasthenia gravis, or multiple sclerosis (Wu et al. 2009). The effect of Ampyra on improving bladder emptying was tested much earlier by Maggi et al., in urethane-anesthetized rats (Maggi et al. 1988). Ampyra potentiated nerve-evoked bladder contractions, and intravenous injection in the dose ranging from 0.15 to 2 mg/kg i.v. produced a dose-dependent potentiation of voiding frequency and activation of high-amplitude, hexamethonium-sensitive rhythmic bladder contractions.

Several types of potassium currents have been characterized in the bladder, but the subtype of K_v is considered to play an important role in spontaneous activity by regulating the resting membrane potential of smooth muscles and for repolarizing the action potential (Petkov 2012). Other types include BK channels that control action potential duration and the resting membrane potential, whereas SK currents underlie after-hyperpolarizations (Thorneloe and Nelson 2003). KCNQ (K_v7) currents are outwardly rectifying, voltage-dependent K⁺ currents that activate at potentials positive to −60 mV with little inactivation (Gribkoff 2008; Gu et al. 2005). Five genes encoding the KCNQ family of ion channel proteins have been identified, each encoding a different KCNQ α-subunit (1–5). KCNQ are considered important in the regulation of smooth muscle contractility and tone (Anderson et al. 2013). KCNQ subtypes 1–5 are functionally expressed in detrusor smooth muscle as KCNQ channel inhibitors XE991, linopirdine, or chromanol 293B increased the amplitude of tetrodotoxin TTX-insensitive myogenic spontaneous contractions (Anderson et al. 2013). KCNQ inhibition by XE991 depolarized the cell membrane and evoked transient depolarizations in quiescent cells. XE991 also increased the frequency of Ca²⁺-oscillations in detrusor smooth muscles of guinea pig bladder (Anderson et al. 2013). On the other hand, spontaneous activity was inhibited by the KCNQ channel activators flupirtine or meclofenamic acid (Anderson et al. 2013), and, in a separate study, another KCNQ activator, retigabine, decreased the capsaicin-induced bladder overactivity in a freely moving, conscious rat (Streng et al. 2004). Taken together, blockade of KCNQ locally in the bladder is a potential approach for UAB.