LUTS (2012) 4, 4855

REVIEW ARTICLE

Pathophysiology of Overactive Bladder

En MENG,1 Wei-Yu LIN,2 Wei-Chia LEE,3 and Yao-Chi CHUANG3
Department of Urology, Tri-Service General Hospital, National Defense Medical Center, Taipei, 2 Department of Urology, Chia Yi Chang Gung Memorial Hospital, Chiayi, and 3 Department of Urology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
1

Overactive bladder syndrome (OAB), characterized by urinary frequency, nocturia and urgency with or without incontinence, is a widespread medical condition with signicant impact on quality of life. Three main factors have been proposed regarding the cause of OAB: myogenic, neurogenic and urotheliogenic. Disturbance of any of the three factors or a combination of these factors can attribute to OAB. Metabolic derangement, bladder outlet obstruction and inammation can increase the excitability of nerve, detrusor muscle and alter the sensory and barrier functions of the urothelium. The detection of proteins in the urine such as NGF, PGE2, and proinammatory chemokines may advance our understanding of the pathophysiology of OAB and offer novel diagnostic biomarkers of OAB. Key words overactive bladder, pathophysiology, urothelium, metabolic syndrome, inammation
1. INTRODUCTION

Overactive bladder syndrome (OAB) is a common medical condition with signicant impact on quality of life across the world. It is characterized by urinary frequency, nocturia and urgency with or without incontinence.1 It has been estimated that the prevalence of OAB was 10.7% in the worldwide population in 2008, and will increase to 20.1% in 2018.2 It occurs more frequently in women than in men, and its incidence increases with age.3 Although many basic and clinical studies have been performed, the cause of OAB remains to be established.4 The mainstay of current pharmacological treatment involves the use of muscarinic antagonists, but their therapeutic effectiveness is limited by a combination of limited efcacy and troublesome side-effects.5,6 Therefore, nding the etiology of OAB is important for developing effective treatments. Here we review recent research in the pathophysiology of OAB and focus on bladder outlet obstruction (BOO), metabolic syndrome and inammation (Fig. 1)
2. MYOGENIC, NEUROGENIC AND UROTHELIOGENIC FACTORS

enhanced intravesical pressure during voiding may result in periodic ischemia of the bladder resulting in damage to some intrinsic neurons in the bladder wall and secondary changes in smooth muscle properties over time.8,9 These changes may then increase excitability and electrical coupling between cells. A local contraction occurring in any part of the detrusor will then spread throughout the bladder wall, resulting in coordinated myogenic contraction of the entire bladder.7,10,11 In addition, partial denervation of the detrusor may cause supersensitivity of detrusor to neurotransmitters, which consequently augments the response to stimulation.12 Sui et al. recently demonstrated that spontaneous, autonomous cellular activityCa2+ and membrane potential oscillations, originates from human detrusor smooth that is mediated by extracellular Ca2+ inux and intracellular release.13 Such cellular activity underlies spontaneous muscle contraction and defective Ca2+ activation contributes to upregulated contractile activity in overactive bladders.
2.2. Neurogenic factor

Three main factors have been proposed regarding the cause of OAB: myogenic, neurogenic and urotheliogenic.
2.1. Myogenic factor

The neurogenic factor suggests that damage to central inhibitory pathways in the brain and spinal cord or sensitization of peripheral afferent terminals in the

The myogenic factor was best explained by Brading7 who stated that alterations in the properties of the detrusor myocytes are a necessary prerequisite for the production of an involuntary detrusor contraction, which in turn causes an unstable increase of intravesical pressure. It has been recently reported that events leading to

Correspondence: Yao-Chi Chuang, MD, 123 Ta Pei Road, Niao Song Hsiang,

Kaohsiung Hsien, 83301, Taiwan. Tel: (886) 7-7317123; Fax: (886) 7-7318762. Email: chuang82@ms26.hinet.net Received 19 August 2011; revised 27 October 2011; accepted 11 November 2011.
DOI: 10.1111/j.1757-5672.2011.00122.x

2012 Blackwell Publishing Asia Pty Ltd

Pathophysiology of OAB

49

Fig. 1 Possible pathophysiology of overactive bladder. Ach, acetylcholine; ATP, adenosine triphosphate; BOO, bladder outlet obstruction; DM, diabetes mellitus; NGF, nerve growth factor; TRPV1, transient receptor potential vanilloid 1.

bladder can unmask primitive voiding reexes that trigger detrusor overactivity. This can result from damage to the brain, which can induce detrusor overactivity by suppressing suprapontine inhibition; damage to axonal pathways in the spinal cord leads to the emergence of primitive spinal bladder reexes triggered by C-ber bladder afferent neurons.14 Neurogenic causes may be seen in patients who have multiple sclerosis, cerebrovascular events and Parkinsons disease. Kessler et al. reported that thalamic deep brain stimulation resulted in an earlier desire to void and decreased bladder capacity,15 suggesting a regulatory role of the thalamus in lower urinary tract function. Recent brain imaging studies have also demonstrated that bladder control depends on an extensive network of brain regions, and dysfunction in various parts may contribute to urge incontinence.16 Abnormality in nonadrenergic noncholinergic (NANC) neurotransmission may also cause OAB. OReilly et al. were unable to detect a purinergic component of nerve-mediated contractions in control (normal) human bladder preparations but found an approximately 50% purinergic-mediated component in OAB specimens.17 They concluded that this abnormal purinergic transmission in the bladder might explain symptoms in OAB patients. Afferent innervations locating within the suburothelial layer of the bladder wall have been attracting research interest recently. Numerous stimulatory and inhibitory mediators and neurotransmitters may be released from the urothelium and interact with a variety of specialized receptors and participate in signal transduction leading to wider neuroactivation. Dysregulation of bladder afferent activity leads to altered micturition signaling within bladder efferent pathways and consequently causes impaired detrusor function.18 Yamaguchi et al. hypothesized that OAB may be more accurately dened as a hypersensitivity disorder rather than a syndrome characterized primarily by urgency.19
2012 Blackwell Publishing Asia Pty Ltd

By using a rat model, De Laet et al. suggested that oxybutynin may directly or indirectly inuence bladder sensory nerves, inhibiting the afferent part of the micturition reex.20 Another study demonstrated that 3 -AR agonist CL316,243, can inhibit mechanosensitive A delta-bers, but not C-bers, of primary bladder afferents of the rat. In addition, 3 -AR agonist CL316,243 can inhibit PGE(2)induced C-ber hyperactivity.21 Oxidative stress induced by H2 O2 has recently been demonstrated to activate capsaicin-sensitive C-ber afferent pathways, thereby inducing detrusor overactivity.22 Research focusing on developing afferent nerve blockers may therefore discover fruitful new treatments for OAB. A novel positive modulator of calcium-activated K+ channels of small and intermediate conductance, 4,5-dichloro1,3-diethyl-1,3-dihydro-benzoimidazol-2-one (NS4591), which activate small conductance K+ channels in acutely dissociated bladder primary afferent neurons, has been demonstrated as an effective compound in animal models of bladder overactivity.22

2.3. Urotheliogenic factor

Increasing evidence has suggested that the urothelium is not just a passive barrier, but is also is a responsive structure that is capable of detecting thermal, mechanical and chemical stimuli. Transmitters released from the urothelium may alter the excitability of afferent nerves and affect detrusor muscle contractility23,24 (Fig. 2). Absence of the urothelium may cause an increase in the spontaneous activity of detrusor.25 Shioyama et al. reported that chronic urothelial injury leads to an increase in urinary frequency and a decrease in voiding volume.26 Thus the urothelium is an important participant in the pathophysiology of OAB.

50

En Meng et al.

2.4. BOO and OAB

Fig. 2 Urothelium may synthesize and release multiple neurotransmitters which consequently alter the excitability of afferent nerves and affect the detrusor muscle contractility. Ach, acetylcholine; ATP, adenosine triphosphate; M, muscarinic receptors (M2 , M3 ); N, nicotinic receptors; TRPV1, transient receptor potential vanilloid 1.

Urothelial cells express ion channels similar to stretch activated (mechanosensitive) channels in nervous tissue and these channels may play a role in mechanotransduction in the lower urinary tract. The epithelial sodium channel (ENaC) has been implicated in several processes including transduction of mechanical and nociceptive stimuli.27 The transient receptor potential vanilloid 1 (TRPV1), a Ca2+ -permeable, non-selective cation channel, which has a prominent role in nociception, is present in urothelial cells and underlies their sensitivity to vanilloid compounds.28 Exogenous application of capsaicin or resiniferatoxin increases intracellular calcium and evokes transmitter (NO, ATP) release in cultured urothelial cells. These responses were eliminated in TRPV1 null mice,29 indicating that TRPV1 is essential in mediating the responses of the urothelium in intravesical chemical stimulation. Although only TRPV1 has been extensively studied so far, the role of other TRP channels suggests interesting new targets to focus on.30 A recent study demonstrated that the urothelium synthesizes and releases acetylcholine (Ach) which differs widely from that of neurons with respect to the molecular components of ACh synthesis and release machinery. Thus, urothelium and nerves might be targeted differently by pharmacologic approaches to OAB.31 Chuang et al. reported that human urine obtained after taking solifenacin prevented carbachol-induced detrusor overactivity. The authors concluded that urine excreted after oral ingestion of solifenacin may act at the urothelium and provide a localized pharmacological advantage for the treatment of OAB.32 Possible causes of OAB include damage of intrinsic neurons resulting in altered properties of smooth muscle cells, decreased suppression of suprapontine inhibition, abnormal peripheral NANC neurotransmission, increased afferent activity and changes in urothelial signaling. The true cause of OAB and detrusor overactivity may be different in different individuals, and may include one or more of the above and possibly other mechanisms that are yet to be described.

Urodynamic studies of patients with lower urinary symptoms diagnosed BOO in 3168% of patients with OAB.33 36 The preoperative incidence of OAB varies from 25% in patients without BOO to 62% in those with BOO.37,38 The 2531% of OAB patients who underwent transurethral resection of prostate had persistent OAB symptoms.33,34,36 However, the rate of de novo OAB has been reported to be at most 10% in patients who have had a prostatectomy.34,37,39 BOO-induced OAB has been attributed to change in NGF, TREK1, K+ channel, muscarinic, and purinergic receptors. Changes in afferent nerves are associated with irritative symptoms. Nerve growth factor (NGF) is a secretory protein that is fundamental in the development of the peripheral nervous system.40,41 Previous studies have shown that NGF participates in target organneuronal interactions resulting in neural plasticity in a BOO model in rats.40,41 TRPV1 is expressed not only by afferent nerves that shape close contact with the bladder, but also by urothelial cells.29,42 Therefore, changes in NGF and TRPV1 expression in the bladder may inuence sensory signaling and affect persistent irritative symptoms in unstable bladder after relief of BOO.43 TREK-1 is a proposed molecular candidate for stretchdependent K(+) channels SDK channel, which is mechanosensitive and stabilizes detrusor myocyte membrane potential during bladder lling. TREK-1 may help the bladder wall to relax during lling to accommodate urine at low pressure.44 A study in BOO mice showed that the expression of TREK-1 channel protein and immunoreactivity was signicantly decreased in bladder smooth muscle.45 L-methioninol, a TREK-1 channel blocker, induced a signicant increase in premature contractions during the lling phase in sham operated mice. However, L-methioninol had no signicant effect in obstructed mice, which showed an overactive detrusor phenotype. These results demonstrated that downregulation of TREK-1 channel in detrusor myocytes is associated with OAB in a murine model of BOO.45 Stabilizing membrane potential and reducing excitability of nerves and muscle cells are important functions of K+ channel.46 Several studies have reported on the relationship between OAB and K+ channel.47 51 Several modulators of these K+ channels have been developed as potential treatment of OAB.52 54 Kita et al. investigated the effects of BOO on the expression and function of large conductance (BK) and small conductance (SK) Ca2+ -activated K+ channels in detrusor smooth muscle in rats with 6-week BOO.55 The expression of the BK channel 1-subunit and the SK3 channel was remarkably increased in obstructed bladders. However, the expression of the BK channel 4-subunit was decreased as the severity of BOO-induced OAB progressed. These results advocate that long-term exposure to BOO for 6 weeks augments 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
2012 Blackwell Publishing Asia Pty Ltd

Pathophysiology of OAB

51

be a compensatory mechanism to reduce BOO-induced OAB.55 Activation of muscarinic receptors on the detrusor is one of the mechanisms of detrusor contraction. In addition, evidence showed that urothelial cells express muscarinic receptors,56 and that urothelial/suburothelial muscarinic receptors play a role in the etiology of OAB or sensory urgency.57,58 The P2X receptor is an ATPgated ion channel that is probably composed of three protein subunits.59,60 ATP, released by stretched urothelial cells, acts on P2X3 receptors on suburothelial sensory afferents.61,62 Intravesical instillation of ATP induces OAB in conscious freely moving rats, further supporting a role for ATP in urothelial signaling. A previous study on immunouorescence staining showed that muscarinic and purinergic receptors were co-localized in both the urothelium and the muscle layer.63 Immunoreactivity and Western blotting showed that the expression of M2 , M3 and P2X3 receptors was increased in the urothelium of BOO rats. Also, there was increased M3 receptor expression in the muscle layer of the BOO group.63 These results proposed that changes in urothelium receptor expression could have a role in mediating the afferent sensory responses in the urinary bladder.63
3. METABOLIC SYNDROME, DIABETES AND OAB

The prevalence of metabolic syndrome in the adult population is approximately 23%.64 Both OAB and metabolic syndrome have high prevalence in the population and affect public health profoundly. Metabolic syndrome consists of the risk factors of cardiovascular disease, diabetes, insulin resistance, central obesity, dyslipidemia and hypertension.65 67 In an epidemiological study, Rohrmann et al. reported that men with metabolic syndrome had an increased risk of nocturia, incomplete bladder emptying, weak stream and hesitancy.68 Yu et al. indicated that hyperlipidemia is associated with OAB in Taiwanese women.69 Furthermore, obesity alone or combing with diabetes can precipitate lower urinary tract dysfunction, such as OAB and stress urinary incontinence in women.70 The impact of diabetes on the lower urinary tract is multifactorial, including osmolarity diuresis effect, metabolic perturbation, and neuropathy. Diabetes may cause dysfunctions of smooth muscle, urothelium and neuronal components of the bladder.71,72 In a survey of 1359 consecutive DM subjects, 22.5% reported having OAB with 11.7% reporting OAB dry and 10.8% with OAB wet.73 The male gender (24.8%) was more commonly associated with OAB than female gender (20.1%) in DM population with a mean age of 60 years.73 Diabetic men had a larger prostate than the non-diabetic group.74 Men aged 60 years or above had a high prevalence of benign prostatic hyperplasia, which often caused BOO and contributed to the presence OAB. The impact of diabetes on bladder function was observed in a model of streptozocin-induced diabetic rats. In the early stage of diabetic bladder dysfunction, remodeling of the bladder wall occurs.75,76 The diuresis
2012 Blackwell Publishing Asia Pty Ltd

and metabolic effects of diabetes result in detrusor hypertrophy and mechanical property changes, which cause a decrease in bladder voiding efciency. The early stage of diabetic vesical neuropathy also contributes to the development of detrusor overactivity. Increased expression of M2 and M3 receptors in uroepithelium and bladder muscle layer were observed in 2-week-old streptozocininduced diabetic rats.77,78 However, in patients with classic diabetic cystopathy, decreased bladder sensation and urodynamic detrusor underactivity are seen and may explain why some patients with diabetic bladder dysfunction can have reduced urgency. In an animal model of metabolic syndrome induced by fructose feeding, Tong et al. reported that upregulation of M2,3 -muscarinic receptors in the bladder were associated with DO.79 The metabolic perturbations induced by long-term fructose feeding also contributed to DO and OAB symptoms, including proinammation, increased oxidative stress, mitochondria dysfunction, an increase of apoptosis in the detrusor muscle, and detrusor hypertrophy.80,81 In a spontaneously hypertensive and hyperlipidemic rat model, Nobe et al. also indicated decreased Rho kinase and protein kinase activities, which weaken detrusor contractility.82 It has been shown that heritable hyperlipidemia can cause reduced bladder capacity, DO and nerve degeneration in a chronic hyperlipidemic rabbit model.83 This observation may explain the increase of OAB symptoms in patients with hyperlipidemia.70 Azadoi et al. reported that the hypercholesterolemia concurrent with atherosclerosis causes ischemic bladder and DO.84,85 The authors suggested that internal iliac vessel remodeling induced by hypercholesterolemia and endothelial injuries play a role in the development of OAB. Furthermore, increased proinammation cytokines and leukotrienes could increase smooth muscle contraction and induce bladder hyperactivity. Hypertension, hyperinsulinemia and obesity are associated with autonomic hyperactivity. It is well-known that autonomic hyperactivity can induce bladder neck dysfunction and LUTS.86 Detrusor hypertrophy is another common phenomenon that can be observed in animal models of metabolic syndrome and diabetes.75,79,81 It has been shown that detrusor hypertrophy is concurrent with decreased functional bladder capacity and increase of urinary frequency in a fructose-fed rat model. Detrusor hypertrophy is ordinarily associated with poor compliance, high intravesical pressure as well as DO, which might reduce bladder blood ow signicantly.87 It was followed by cyclic ischemiareperfusion injuries, and increased reactive nitrogen species. Oxidative stress is induced by over- exercise of the detrusor in the course of repeat DO and urinary frequency.85,88 Mitochondrial apparatus could supply high-energy consumption in the early stages of bladder hyperactivity. In the long run, excessive energy demand and stimulation could exhaust the mitochondrial respiratory chain and impair its energy transduction system. Under such circumstances, oxidatively strained mitochondria become deformed and turn to a source of

52

En Meng et al.

reactive oxidative stress, which initiates a self-destructing process in the mitochondrial respiratory apparatus, leading to protein damage, detrusor dysfunction, and ultimately atrophy.

4. INFLAMMATION AND OAB

C-reactive protein (CRP) is produced and secreted by the liver in response to inammatory processes occurring in the body. The association of elevated serum CRP with various lower urinary tract symptoms (LUTS) suggests a possible role of inammation. Kupelian et al. analyzed data from 1898 men and 1854 women who participated in the Boston Area Community Health study and had complete data on CRP levels.89 They found the prevalence of OAB increased with CRP levels in both genders. Chuang et al. also showed that serum CRP level was signicantly higher in OAB wet patients compared with control (2.96 0.47 vs 0.93 0.27 mg/L, P < 0.01) and OAB dry (2.96 0.47 vs 1.06 0.16 mg/L, P < 0.05).90 NGF plays a key role in the survival of sensory neurons during development and is necessary throughout adulthood for maintenance of the normal properties of small-sized afferent neurons with unmyelinated axons (i.e. C-ber afferents). There is also growing evidence that NGF is a peripheral mediator of several types of inammatory painful conditions.91,92 NGF is a target-derived trophic factor synthesized in the bladder and taken up by sensory nerves to be transported to the spinal cord in retrograde fashion. Intravesical administration of exogenous NGF in animals can facilitate afferent ring and produce bladder hyperactivity, which is blocked by antiNGF.93,94 Overexpression of NGF in the bladder smooth muscle in spontaneously hypertensive rats leads to hyperinnervation of the bladder, which results in hyperactive voiding behavior.95 Stretching of the urothelium might induce production of NGF in the bladder tissue and secretion into the urine. Elevated urinary NGF levels play an important role in mediating the sensation of urgency in OAB. Therefore, NGF production can serve as a biomarker for neuroplasticity the some common pathway involved in the pathogenesis of OAB. Prostaglandin E2 (PGE2 ) synthesized in bladder muscle and mucosa has a complex local action in the bladder. PGE2 affects the normal micturition reex and under pathophysiological conditions (e.g. mucosa injury and inammatory mediators).96 Intravesical administration of PGE2 stimulates reex micturition through activation of capsaicin sensitive afferent nerves and causes bladder overactivity in rats and in humans.97,98 A previous study has suggested the association of inammation with OAB symptoms by the signicant elevation of NGF and PGE2 levels in the urine of OAB patients.99 Liu et al. showed that urine NGF levels were very low in normal controls, while patients with OAB had signicantly higher urinary NGF levels.100 Furthermore, OAB wet patients had signicantly higher urinary NGF levels than OAB dry patients. This study concluded that elevated urinary NGF levels play an important role

in mediating the sensation of urgency in OAB. The possible reason for the difference of NGF levels between OAB dry and OAB wet is the higher percentage of DO in patients with OAB wet. Furthermore, urine NGF level was decreased in association with the reduction of urgency severity in OAB patients who responded to intravesical botulinum toxin A injection or oral antimuscarinic therapy,101,102 but not in non-responders. These results support urinary NGF level as a potential biomarker for evaluating a therapeutic outcome for OAB. Tyagi et al. collected midstream urine specimens from eight asymptomatic control subjects and 17 idiopathic OAB patients.103 The urine was analyzed by a multiplex panel screen for 12 chemokines, cytokines, growth factors, and soluble receptors using Luminex multiplex ELISA technology (xMAP technology, Affymetrix, Inc. Santa Clara, CA, USA). This analysis revealed a signicant elevation of seven key inammatory proteins in the urine of OAB patients relative to controls. This reported urinary chemokines prole in OAB patients corroborates the inference of severe inammation in such patients.103 In a study of 179 biopsies obtained from 79 patients, 123 (63.1%) from 51 NDO patients and 56 (26.9%) from 28 IDO patients, Apostolidis et al. revealed signs of chronic inammation were found in 59.1% of baseline biopsies (65.6% of NDO vs 50% of IDO, p = 0.049). The results also suggest the role of inammation in OAB pathology.104
5. CONCLUSION

Alterations in nerve and smooth muscle excitability and changes in bladder urothelium orchestrated by neurotrophins, sensory receptors, and specic ion channels are temporally linked with OAB. Metabolic effects, inammatory reaction, and BOO contribute to the pathophysiology of OAB. The realization that OAB may arise from different etiologies with various molecular changes offers novel avenues for therapeutic intervention.
DISCLOSURE

The authors declare no conict of interest. Chuang Y.C. is a lecturer for Pzer, Astellas, GSK, and Lilly.
REFERENCES
1. Abrams P, Cardozo L, Fall M et al. The standardisation of terminology of lower urinary tract function: report from the standardization sub-committee of the international continence society. Neurourol Urodyn 2002; 21: 16778. 2. Irwin DE, Kopp ZS, Agatep B, Milsom I, Abrams P. Worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. BJU Int 2011; 108: 11328 [Epub ahead of print]. 3. Irwin DE, Milsom I, Hunskaar S et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in ve countries: results of the EPIC study. Eur Urol 2006; 50: 130615. 4. Hashim H, Abrams P. Overactive bladder: an update. Curr Opin Urol 2007; 17: 2316. 5. Brading AF. Acetylcholine and the overactive bladder. Eur Urol 2007; 51: 8813. 2012 Blackwell Publishing Asia Pty Ltd

Pathophysiology of OAB 6. Herbison P, Hay-Smith J, Ellis G, Moore K. Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. Br Med J 2003; 326: 8414. 7. Brading AF. A myogenic basis for the overactive bladder. Urology 1997; 50: 5767; discussion 6873. 8. Brading A. Overactive bladder: why it occurs. Womens Health Med 2005; 2: 203. 9. Brading AF, Symes S. Ischemia as an etiological factor in bladder instability: implications for therapy. Adv Exp Med Biol 2003; 539: 25569. 10. German K, Bedwani J, Davies J, Brading AF, Stephenson TP. Physiological and morphometric studies into the pathophysiology of detrusor hyperreexia in neuropathic patients. J Urol 1995; 153: 167883. 11. Mills IW, Greenland JE, McMurray G et al. Studies of the pathophysiology of idiopathic detrusor instability: the physiological properties of the detrusor smooth muscle and its pattern of innervation. J Urol 2000; 163: 64651. 12. Sibley GN. Developments in our understanding of detrusor instability. Br J Urol 1997; 80(Suppl 1): 5461. 13. Sui G, Fry CH, Malone-Lee J, Wu C. Aberrant Ca2+ oscillations in smooth muscle cells from overactive human bladders. Cell Calcium 2009; 45: 45664. 14. de Groat WC. A neurologic basis for the overactive bladder. Urology 1997; 50: 3652; discussion 5356. 15. Kessler TM, Burkhard FC, ZBrun S et al. Effect of thalamic deep brain stimulation on lower urinary tract function. Eur Urol 2008; 53: 60712. 16. Grifths D, Tadic SD. Bladder control, urgency, and urge incontinence: evidence from functional brain imaging. Neurourol Urodyn 2008; 27: 46674. 17. OReilly BA, Kosaka AH, Knight GF et al. P2X receptors and their role in female idiopathic detrusor instability. J Urol 2002; 167: 15764. 18. Yoshimura N. Lower urinary tract symptoms (LUTS) and bladder afferent activity. Neurourol Urodyn 2007; 26: 90813. 19. Yamaguchi O, Honda K, Nomiya M et al. Dening overactive bladder as hypersensitivity. Neurourol Urodyn 2007; 26: 9047. 20. De Laet K, De Wachter S, Wyndaele JJ. Systemic oxybutynin decreases afferent activity of the pelvic nerve of the rat: new insights into the working mechanism of antimuscarinics. Neurourol Urodyn 2006; 25: 15661. 21. Aizawa N, Igawa Y, Nishizawa O, Wyndaele JJ. Effects of CL316,243, a beta 3-adrenoceptor agonist, and intravesical prostaglandin E2 on the primary bladder afferent activity of the rat. Neurourol Urodyn 2010; 29: 7716. 22. Hougaard C, Fraser MO, Chien C et al. A positive modulator of K Ca 2 and K Ca 3 channels, 4,5-dichloro-1,3-diethyl1,3-dihydro-benzoimidazol-2-one (NS4591), inhibits bladder afferent ring in vitro and bladder overactivity in vivo. J Pharmacol Exp Ther 2009; 328: 2839. 23. Maggi CA, Santicioli P, Parlani M, Astol M, Patacchini R, Meli A. The presence of mucosa reduces the contractile response of the guinea-pig urinary bladder to substance P. J Pharm Pharmacol 1987; 39: 6535. 24. Birder LA, de Groat WC. Mechanisms of disease: involvement of the urothelium in bladder dysfunction. Nat Clin Pract Urol 2007; 4: 4654. 25. Meng E, Young JS, Brading AF. Spontaneous activity of mouse detrusor smooth muscle and the effects of the urothelium. Neurourol Urodyn 2008; 27: 7987. 26. Shioyama R, Aoki Y, Ito H et al. Long-lasting breaches in the bladder epithelium lead to storage dysfunction with increase in bladder PGE2 levels in the rat. Am J Physiol Regul Integr Comp Physiol 2008; 295: R7148. 27. Wang EC, Lee JM, Johnson JP, Kleyman TR, Bridges R, Apodaca G. Hydrostatic pressure-regulated ion transport in bladder uroepithelium. Am J Physiol Renal Physiol 2003; 285: F65163. 2012 Blackwell Publishing Asia Pty Ltd

53

28. Birder LA, Kanai AJ, de Groat WC et al. Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci USA 2001; 98: 13396401. 29. Birder LA, Nakamura Y, Kiss S et al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nat Neurosci 2002; 5: 85660. 30. Everaerts W, Gevaert T, Nilius B, De Ridder D. On the origin of bladder sensing: Tr(i)ps in urology. Neurourol Urodyn 2008; 27: 26473. 31. Lips KS, Wunsch J, Zarghooni S et al. Acetylcholine and molecular components of its synthesis and release machinery in the urothelium. Eur Urol 2007; 51: 104253. 32. Chuang YC, Thomas CA, Tyagi S, Yoshimura N, Tyagi P, Chancellor MB. Human urine with solifenacin intake but not tolterodine or darifenacin intake blocks detrusor overactivity. Int Urogynecol J Pelvic Floor Dysfunct 2008; 19: 13537. 33. Abrams PH, Farrar DJ, Turner-Warwick RT et al. The results of prostatectomy: a symptomatic and urodynamic analysis of 152 patients. J Urol 1979; 121: 6402. 34. de Nunzio C, Franco G, Rocchegiani A et al. The evolution of detrusor overactivity after watchful waiting, medical therapy and surgery in patients with bladder outlet obstruction. J Urol 2003; 169: 5359. 35. Seki N, Kai N, Seguchi H et al. Predictives regarding outcome after transurethral resection for prostatic adenoma associated with detrusor underactivity. Urology 2006; 67: 30610. 36. Van Venrooij GE, Van Melick HH, Eckhardt MD et al. Correlations of urodynamic changes with changes in symptoms and well-being after transurethral resection of the prostate. J Urol 2002; 168: 6059. 37. Housami F, Abrams P. Persistent detrusor overactivity after transurethral resection of the prostate. Curr Urol Rep 2008; 9: 28490. 38. Price DA, Ramsden PD, Stobbart D et al. The unstable bladder and prostatectomy. Br J Urol 1980; 52: 52931. 39. Seaman EK, Jacobs BZ, Blaivas JG et al. Persistence or recurrence of symptoms after transurethral resection of the prostate: a urodynamic assessment. J Urol 1994; 152: 9357. 40. Steers WD, De Groat WC. Effect of bladder outlet obstruction on micturition reex pathways in the rat. J Urol 1988; 140: 86471. 41. Steers WD, Kolbeck S, Creedon D et al. Nerve growth factor in the urinary bladder of the adult regulates neuronal form and function. J Clin Invest 1991; 88: 170915. 42. Caterina MJ, Schumacher MA, Tominaga M et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997; 389: 81624. 43. Kim JC, Kim DB, Seo SI et al. Nerve growth factor and vanilloid receptor expression, and detrusor instability, after relieving bladder outlet obstruction in rats. BJU Int 2004; 94: 9158. 44. Baker SA, Hatton WJ, Han J et al. Role of TREK-1 potassium channel in bladder overactivity after partial bladder outlet obstruction in mouse. J Urol 2010; 183: 793800. 45. Baker SA, Hennig GW, Han J et al. Methionine and its derivatives increase bladder excitability by inhibiting stretchdependent K(+) channels. Br J Pharmacol 2008; 153: 125971. 46. Salkoff L, Butler A, Ferreira G et al. High-conductance potassium channels of the SLO family. Nat Rev Neurosci 2006; 7: 92131. 47. Herrera GM, Pozo MJ, Zvara P et al. Urinary bladder instability induced by selective suppression of the murine small conductance calcium-activated potassium (SK3) channel. J Physiol 2003; 551 (Pt 3): 893903. 48. Meredith AL, Thorneloe KS, Werner ME et al. Overactive bladder and incontinence in the absence of the BK large conductance Ca2+-activated K+ channel. J Biol Chem 2004; 279: 3674652.

54

En Meng et al. 69. Yu HJ, Liu CY, Lee KL, Lee WC, Chen THH. Overactive bladder syndrome among community-dwelling adults in Taiwan: prevalence, correlates, perception, and treatment seeking. Urol Int 2006; 77: 32733. 70. Lawrence JM, Lukacz ES, Liu IL, Nager CW, Luber KM. Pelvic oor disorders, diabetes, and obesity in women: ndings from the Kaiser Permanente Continence Associated Risk Epidemiology Study. Diabet Care 2007; 30: 253641. 71. Lee WC, Wu CC, Wu HP, Tai TY. Lower urinary tract symptoms and uroowmetry in women with type 2 diabetes mellitus with and without bladder dysfunction. Urology 2007; 69: 68590. 72. Lee WC. The impact of diabetes on the lower urinary tract dysfunction. JTUA 2009; 20: 15561. 73. Liu RT, Chung MS, Lee WC et al. Prevalence of Overactive Bladder (OAB) and associated risk factors in 1,359 patients with type 2 diabetes. Urology 2011; 78: 10405. 74. Steers WD. An enlarged prostate is diagnosed more often in patients with type 2 diabetes. Rev Urol 2002; 4: S718. 75. Liu G, Daneshgari F. Alterations in neurogenically mediated contractile responses of urinary bladder in rats with diabetes. Am J Physiol Renal Physiol 2005; 288: F12206. 76. Wang CC, Nagatomi J, Toosi KK et al. Diabetes-induced alternations in biomechanical properties of urinary bladder wall in rats. Urology 2009; 73: 9115. 77. Tong YC, Cheng JT, Hsu CT. Alterations of M(2)-muscarinic receptor protein and mRNA expression in the urothelium and muscle layer of the streptozotocin-induced diabetic rat urinary bladder. Neurosci Lett 2006; 406: 21621. 78. Cheng JT, Yu BC, Tong YC. Changes of M3-muscarinic receptor protein and mRNA expressions in the bladder urothelium and muscle layer of streptozotocin-induced diabetic rats. Neurosci Lett 2007; 423: 15. 79. Tong YC, Cheng JT. Alterations of M2,3-muscarinic receptor protein and mRNA expression in the bladder of the fructose fed obese rat. J Urol 2007; 178: 153742. 80. Lee WC, Chien CT, Yu HJ, Lee SW. Bladder dysfunction in rats with metabolic syndrome induced by long-term fructose feeding. J Urol 2008; 179: 24706. 81. Lee WC, Chuang YC, Chiang PH, Chien CT, Yu HJ, Wu CC. Pathophysiological studies of overactive bladder and bladder motor dysfunction in a rat model of metabolic syndrome. J Urol 2011; 186: 31825. 82. Nobe K, Yamazaki T, Kumai T et al. Alterations of glucosedependent and -independent bladder smooth muscle contraction in spontaneously hypertensive and hyperlipidemic rat. J Pharmacol Exp Ther 2008; 324: 63142. 83. Yoshida M, Masunaga K, Nagata T, Satoji Y, Shiomi M. The effects of chronic hyperlipidemia on bladder function in myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits. Neurourol Urodyn 2010; 29: 13504. 84. Azadzoi KM, Shinde VM, Tarcan T et al. Increased leukotriene and prostaglandin release, and overactivity in the chronically ischemic bladder. J Urol 2003; 169: 188591. 85. Azadzoi KM, Radisavljevic ZM, Golabek T et al. Oxidative modication of mitochondrial integrity and nerve ber density in the ischemic overactive bladder. J Urol 2010; 183: 3629. 86. Yang SSD, Wang CC, Hsieh JH, Chen YT. 1-Adrenergic blockers in young men with primary bladder neck obstruction. J Urol 2002; 168: 5714. 87. Kershen RT, Azadzoi KM, Siroky MB. Blood ow, pressure and compliance in the male human bladder. J Urol 2002; 168: 1215. 88. Di Meo S, Venditti P. Mitochondria in exercise-induced oxidative stress. Biol Signals Recept 2001; 10: 12540. 89. Kupelian V, McVary KT, Barry MJ et al. Association of C-reactive protein and lower urinary tract symptoms in men and women: results from Boston area community health survey. Urology 2009; 73: 9507. 2012 Blackwell Publishing Asia Pty Ltd

49. Petkov GV, Bonev AD, Heppner TJ et al. Beta1-subunit of the Ca2+-activated K+ channel regulates contractile activity of mouse urinary bladder smooth muscle. J Physiol 2001; 537 (Pt 2): 44352. 50. Thorneloe KS, Knorn AM, Doetsch PE et al. Smallconductance, Ca(2+) -activated K+ channel 2 is the key functional component of SK channels in mouse urinary bladder. Am J Physiol Regul Integr Comp Physiol 2008; 294: R173743. 51. Thorneloe KS, Meredith AL, Knorn AM et al. Urodynamic properties and neurotransmitter dependence of urinary bladder contractility in the BK channel deletion model of overactive bladder. Am J Physiol Renal Physiol 2005; 289: F60410. 52. Darblade B, Behr-Roussel D, Oger S et al. Effects of potassium channel modulators on human detrusor smooth muscle myogenic phasic contractile activity: potential therapeutic targets for overactive bladder. Urology 2006; 68: 4428. 53. Malysz J, Buckner SA, Daza AV et al. Functional characterization of large conductance calcium-activated K+ channel openers in bladder and vascular smooth muscle. Naunyn Schmiedebergs Arch Pharmacol 2004; 369: 4819. 54. Pinna C, Sanvito P, Bolego C et al. Effect of the ATPsensitive potassium channel opener Z M226600 on cystometric parameters in rats with ligature-intact, partial urethral obstruction. Eur J Pharmacol 2005; 516: 717. 55. Kita M, Yunoki T, Takimoto K et al. Effects of bladder outlet obstruction on properties of Ca2+-activated K+ channels in rat bladder. Am J Physiol Regul Integr Comp Physiol 2010; 298: R13109. 56. Chess-Williams R. Muscarinic receptors of the urinary bladder: detrusor, urothelial and prejunctional. Auton Autacoid Pharmacol 2002; 22: 13345. 57. Andersson KE, Yoshida M. Antimuscarinics and the overactive detrusorwhich is the main mechanism of action? Eur Urol 2003; 43: 15. 58. de Groat WC. The urothelium in overactive bladder: passive bystander or active participant? Urology 2004; 64(Suppl 1): 711. 59. Jiang LH, Kim M, Spelta V et al. Subunit arrangement in P2X receptors. J Neurosci 2003; 23: 890310. 60. North RA, Surprenant A. Pharmacology of cloned P2X receptors. Annu Rev Pharmacol Toxicol 2000; 40: 56380. 61. Cook SP, McCleskey EW. ATP, pain and a full bladder. Nature 2000; 407: 9512. 62. Zhong Y, Banning AS, Cockayne DA et al. Bladder and cutaneous sensory neurons of the rat express different functional P2X receptors. Neuroscience 2003; 120: 66775. 63. Kim JC, Yoo JS, Park EY et al. Muscarinic and purinergic receptor expression in the urothelium of rats with detrusor overactivity induced by bladder outlet obstruction. BJU Int 2008; 101: 3715. 64. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: ndings from the third National Health and Nutrition Examination Survey. J Am Med Assoc 2002; 287: 3569. 65. Alberti KG, Zimmet PZ. Denition, diagnosis and classication of diabetes mellitus and its complication. Part 1: diagnosis and classication of diabetes mellitus, provisional report of a WHO consultation. Diabet Med 1998; 15: 53953. 66. Balkau B, Charles MA. Comment on the provisional report from the WHO consultation. Diabet Med 1999; 16: 4423. 67. Alberti KG, Zimmet P, Shaw J et al. The metabolic syndromea new worldwide denition. Lancet 2005 Sep 2430; 366(9491): 105962. 68. Rohrmann S, Smit E, Giovannucci E, Platz EA. Association between markers of the metabolic syndrome and lower urinary tract symptoms in the Third National Health and Nutrition Examination Survey (NHANES III). Int J Obes (Lond) 2005; 29: 3106.

Pathophysiology of OAB 90. Chuang YC, Tyagi V, Liu RT, Chancellor MB, Tyagi P. Urine and serum C-reactive protein levels as potential biomarkers of lower urinary tract symptoms. Urol Sci 2010; 21: 1326. 91. McMahon SB, Dmitrieva N, Koltzenburg M. Visceral pain. Br J Anaesth 1995; 75. 92. Dmitrieva N, Shelton D, Rice ASC, McMahon SB. The role of nerve growth factor in a model of visceral inammation. Neuroscience 1997; 78: 44959. 93. Chuang YC, Fraser MO, Yu Y, Chancellor MB, de Groat WC, Yoshimura N. The role of bladder afferent pathways in the bladder hyperactivity induced by intravesical administration of nerve growth factor. J Urol 2001; 165: 9759. 94. Seki S, Sasaki K, Fraser MO et al. Immunoneutralization of nerve growth factor in lumbosacral spinal cord reduces bladder hyperreexia in spinal cord injured rats. J Urol 2002; 168: 226974. 95. Clemow DB, Steers WD, McCarty R, Tuttle JB. Altered regulation of bladder nerve growth factor and neurally mediated hyperactive voiding. Am J Physiol 1998; 275: R127986. 96. Andersson KE, Wein AJ. Pharmacology of lower urinary tract: basis for current and future treatments of urinary incontinence. Pharmacol Rev 2004; 56: 581631. 97. Lee T, Andersson KE, Streng T, Hedlund P. Simultaneous registration of intraabdominal and intravesical pressures during cystometry in conscious ratseffects of bladder outlet obstruction and intravesical PGE2. Neurourol Urodyn 2008; 27: 8895.

55

98. Schussler B. Comparison of the mode of action of prostaglandin E2 (PGE2) and sulprostone, a PGE2-derivative, on the lower urinary tract in healthy women. A urodynamic study. Urol Res 1990; 18: 34952. 99. Kim JC, Park EY, Seo SI, Park YH, Hwang TK. Nerve growth factor and prostaglandins in the urine of female patients with overactive bladder. J Urol 2006; 175: 17736. 100. Liu HT, Kuo HC. Urinary nerve growth factor level could be a potential biomarker for diagnosis of overactive bladder. J Urol 2008; 179: 22704. 101. Liu HT, Chancellor MB, Kuo HC. Urinary nerve growth factor levels are elevated in patients with detrusor overactivity and decreased in responders to detrusor botulinum toxin-A injection. Eur Urol 2009; 56: 7006. 102. Liu HT, Chancellor MB, Kuo HC. Decrease of urinary nerve growth factor levels after antimuscarinic therapy in patients with overactive bladder. BJU Int 2009; 103: 166872. 103. Tyagi P, Barclay D, Zamora R et al. Urine cytokines suggest an inammatory response in the overactive bladder: a pilot study. Int Urol Nephrol 2010; 42: 62935. 104. Apostolidis A, Jacques TS, Freeman A et al. Histological changes in the urothelium and suburothelium of human overactive bladder following intradetrusor injections of botulinum neurotoxin type A for the treatment of neurogenic or idiopathic detrusor overactivity. Eur Urol 2008; 53: 124553.

2012 Blackwell Publishing Asia Pty Ltd